N-(2-(hetaryl)aryl) arylsulfonamides and N-(2-(hetaryl) hetaryl arylsulfonamides

ABSTRACT

Compounds are provided that act as potent antagonists of the CCR9 receptor. Animal testing demonstrates that these compounds are useful for treating inflammation, a hallmark disease for CCR9. The compounds are generally aryl sulfonamide derivatives and are useful in pharmaceutical compositions, methods for the treatment of CCR9-mediated diseases, and as controls in assays for the identification of CCR9 antagonists.

CROSS-REFERENCES TO RELATED APPLICATIONS

The present patent document claims the benefit of the filing dates under35 U.S.C. §119(e) of the following U.S. Provisional Patent ApplicationSer. Nos. 61/046,291, filed Apr. 18, 2008, 60/948,796, filed Jul. 10,2007; and 60/945,849, filed Jun. 22, 2007, each of which is herebyincorporated by reference in its entirety.

FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

The present invention described herein was supported at least in part byNIH (U19-AI056690-01). The government may have certain rights in theinvention.

BACKGROUND

The present invention provides compounds, pharmaceutical compositionscontaining one or more of those compounds or their pharmaceuticallyacceptable salts, which are effective in inhibiting the binding orfunction of various chemokines to chemokine receptors. As antagonists ormodulators of chemokine receptors, the compounds and compositions haveutility in treating various immune disorder conditions and diseases.

Chemokines, also known as chemotactic cytokines, are a group of smallmolecular-weight proteins that are released by a wide variety of cellsand have a variety of biological activities. Chemokines attract varioustypes of cells of the immune system, such as macrophages, T cells,eosinophils, basophils and neutrophils, and cause them to migrate fromthe blood to various lymphoid and none-lymphoid tissues. They mediateinfiltration of inflammatory cells to sites of inflammation, and areresponsible for the initiation and perpetuation of many inflammationdiseases (reviewed in Schall, Cytokine, 3:165-183 (1991), Schall et al.,Curr. Opin. Immunol., 6:865-873 (1994)).

In addition to stimulating chemotaxis, chemokines can induce otherchanges in responsive cells, including changes in cell shape, granuleexocytosis, integrin up-regulation, formation of bioactive lipids (e.g.,leukotrienes), respiratory burst associated with leukocyte activation,cell proliferation, resistance to induction of apoptosis andangiogenesis. Thus, chemokines are early triggers of the inflammatoryresponse, causing inflammatory mediator release, chemotaxis andextravasation to sites of infection or inflammation. They are alsostimulators of a multitude of cellular processes that bear importantphysiological functions as well as pathological consequences.

Chemokines exert their effects by activating chemokine receptorsexpressed by responsive cells. Chemokine receptors are a class ofG-protein coupled receptors, also known as seven-transmembranereceptors, found on the surface of a wide variety of cell types such asleukocytes, endothelial cells, smooth muscle cells and tumor cells.

Chemokines and chemokine receptors are expressed by intrinsic renalcells and infiltrating cells during renal inflammation (Segerer et al.,J. Am. Soc. Nephrol., 11:152-76 (2000); Morii et al., J. DiabetesComplications, 17:11-5 (2003); Lloyd et al. J. Exp. Med., 185:1371-80(1997); Gonzalez-Cuadrado et al. Clin. Exp. Immunol., 106:518-22 (1996);Eddy & Giachelli, Kidney Int., 47:1546-57 (1995); Diamond et al., Am. J.Physiol., 266:F926-33 (1994)).

T lymphocyte (T cell) infiltration into the small intestine and colonhas been linked to the pathogenesis of Coeliac diseases, food allergies,rheumatoid arthritis, human inflammatory bowel diseases (IBD) whichinclude Crohn's disease and ulcerative colitis. Blocking trafficking ofrelevant T cell populations to the intestine can lead to an effectiveapproach to treat human IBD. More recently, chemokine receptor 9 (CCR9)has been noted to be expressed on gut-homing T cells in peripheralblood, elevated in patients with small bowel inflammation such asCrohn's disease and celiac disease. The only CCR9 ligand identified todate, TECK (thymus-expressed chemokine) is expressed in the smallintestine and the ligand receptor pair is now thought to play a pivotalrole in the development of IBD. In particular, this pair mediates themigration of disease causing T cells to the intestine. See for example,Zaballos et al., J. Immunol., 162(10):5671-5675 (1999); Kunkel et al.,J. Exp. Med., 192(5):761-768 (2000); Papadakis et al., J. Immunol.,165(9):5069-5076 (2000); Papadakis et al., Gastroenterology,121(2):246-254 (2001); Campbell et al., J. Exp. Med., 195(1):135-141(2002); Wurbel et al., Blood, 98(9):2626-2632 (2001); and Uehara et al.,J. Immunol, 168(6):2811-2819 (2002); Rivera-Nieves et al.,Gastroenterology, 2006 November; 131(5):1518-29; and Kontoyiannis etal., J. Exp. Med., Vol. 196, Number 12, Dec. 16, 2002. In addition CCR9bearing lymphocytes have been show to mediate the pathology offilariasis (lymphatic filarial disease) and inhibition of CCR9 has beencorrelated with reduction of the pathology associated with suchconditions. See for example Babu et al., Journal of Infectious Diseases,191: 1018-26, 2005.

The identification of compounds that modulate the function of CCR9represents an attractive new family of therapeutic agents for thetreatment of inflammatory and other conditions and diseases associatedwith CCR9 activation, such as inflammatory bowel disease.

PCT Published Application WO 2003/099773 (Millennium Pharmaceuticals,Inc.) discloses compounds which can bind to CCR9 receptors of theformula

PCT Published Application WO 2005/004810 (Merck & Co., Inc.) disclosesbrandykinin B1 antagonists or inverse agonists of the formula

PCT Published Application WO 2005/113513 (ChemoCentryx, Inc.) disclosescompounds that modulate various chemokine receptors.

BRIEF SUMMARY

The present invention is directed to compounds and pharmaceuticallyacceptable salts thereof, compositions, and methods useful in modulatingchemokine activity. The compounds and salts thereof, compositions, andmethods described herein are useful in treating or preventingchemokine-mediated conditions or diseases, including certaininflammatory and immunoregulatory disorders and diseases.

The compounds of the present invention have been shown to modulate oneor more of CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR3,CXCR4, CXCR5, and CX3CR1. In particular, various compounds of thepresent invention modulate CCR9 as shown in the examples.

The compounds of the present invention are represented by formulae(I)-(VIII), (CI)-(CVII) and (CCI)-(CCVI), described below.

In another aspect, the present invention provides compositions useful inmodulating chemokine activity. In one embodiment, a compositionaccording to the present invention comprises a compound according to theinvention and a pharmaceutically acceptable carrier or excipient.

In yet another aspect, the present invention provides methods ofmodulating chemokine function in a cell, comprising contacting the cellwith a therapeutically effective amount of a compound or compositionaccording to the invention.

In still another aspect, the present invention provides methods formodulating chemokine function, comprising contacting a chemokinereceptor with a therapeutically effective amount of a compound orcomposition according to the invention.

In still another aspect, the present invention provides methods fortreating a chemokine-mediated condition or disease, comprisingadministering to a subject a safe and effective amount of a compound orcomposition according to the invention. The administering may be oral,parenteral, rectal, transdermal, sublingual, nasal or topical. In someaspects the compound may be administered in combination with ananti-inflammatory or analgesic agent.

In addition to the compounds provided herein, the present inventionfurther provides pharmaceutical compositions containing one or more ofthese compounds, as well as methods for the use of these compounds intherapeutic methods, primarily to treat diseases associated withchemokine signaling activity.

DETAILED DESCRIPTION

General

The present invention is directed to compounds and salts thereof,compositions and methods useful in the modulation of chemokine receptorfunction, particularly CCR9 function. Modulation of chemokine receptoractivity, as used herein in its various forms, is intended to encompassantagonism, agonism, partial antagonism, inverse agonism and/or partialagonism of the activity associated with a particular chemokine receptor,preferably the CCR9 receptor. Accordingly, the compounds of the presentinvention are compounds which modulate at least one function orcharacteristic of mammalian CCR9, for example, a human CCR9 protein. Theability of a compound to modulate the function of CCR9, can bedemonstrated in a binding assay (e.g., ligand binding or agonistbinding), a migration assay, a signaling assay (e.g., activation of amammalian G protein, induction of rapid and transient increase in theconcentration of cytosolic free calcium), and/or cellular response assay(e.g., stimulation of chemotaxis, exocytosis or inflammatory mediatorrelease by leukocytes).

Abbreviations and Definitions

When describing the compounds, compositions, methods and processes ofthis invention, the following terms have the following meanings, unlessotherwise indicated.

“Alkyl” by itself or as part of another substituent refers to ahydrocarbon group which may be linear, cyclic, or branched or acombination thereof having the number of carbon atoms designated (i.e.,C₁₋₈ means one to eight carbon atoms). Examples of alkyl groups includemethyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl,sec-butyl, cyclohexyl, cyclopentyl, (cyclohexyl)methyl,cyclopropylmethyl, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc.Alkyl groups can be substituted or unsubstituted, unless otherwiseindicated. Examples of substituted alkyl include haloalkyl, thioalkyl,aminoalkyl, and the like. Additional examples of suitable substitutedalkyl include, but are not limited to, hydroxy-isoproptyl, —C(CH₃)₂—OH,aminomethyl, 2-nitroethyl, 4-cyanobutyl, 2,3-dichloropentyl, and3-hydroxy-5-carboxyhexyl, 2-aminoethyl, pentachloroethyl,trifluoromethyl, 2-diethylaminoethyl, 2-dimethylaminopropyl,ethoxycarbonylmethyl, methanylsulfanylmethyl, methoxymethyl,3-hydroxypentyl, 2-carboxybutyl, 4-chlorobutyl, and pentafluoroethyl.Suitable substituents for substituted alkyl, include halogen, —CN,—CO₂R′, —C(O)R′, —C(O)NR′R″, oxo (═O or —O⁻), —OR′, —OC(O)R′,—OC(O)NR′R″—NO₂, —NR′C(O)R″, —NR″′C(O)NR′R″, —NR′R″, —NR′CO₂R″,—NR′S(O)R″, —NR′S(O)₂R″′, —NR″′S(O)NR′R″, —NR″′S(O)₂NR′R″, —SR′,—S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NR′—C(NHR″)═NR′″, —SiR′R″R′″, —N₃,substituted or unsubstituted C₆₋₁₀ aryl, substituted or unsubstituted 5-to 10-membered heteroaryl, and substituted or unsubstituted 3- to10-membered heterocyclyl. The number of possible substituents range fromzero to (2m′+1), where m′ is the total number of carbon atoms in suchradical. With respect to substituted alkyl, R″ and R′″ eachindependently refer to a variety of groups including hydrogen,substituted or unsubstituted C₁₋₈ alkyl, substituted or unsubstitutedC₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkynyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted heterocyclyl, substituted or unsubstituted arylalkyl,substituted or unsubstituted aryloxyalkyl. When R′ and R″ are attachedto the same nitrogen atom, they can be combined with the nitrogen atomto form a 3-, 4-, 5-, 6-, or 7-membered ring (for example, —NR′R″includes 1-pyrrolidinyl and 4-morpholinyl). Furthermore, R′ and R″, R″and R′″, or R′ and R′″ may together with the atom(s) to which they areattached, form a substituted or unsubstituted 5-, 6- or 7-membered ring.

“Alkoxy” refers to —O-alkyl. Examples of an alkoxy group includemethoxy, ethoxy, n-propoxy etc.

“Alkenyl” refers to an unsaturated hydrocarbon group which may belinear, cyclic or branched or a combination thereof. Alkenyl groups with2-8 carbon atoms are preferred. The alkenyl group may contain 1, 2 or 3carbon-carbon double bonds. Examples of alkenyl groups include ethenyl,n-propenyl, isopropenyl, n-but-2-enyl, n-hex-3-enyl, cyclohexenyl,cyclopentenyl and the like. Alkenyl groups can be substituted orunsubstituted, unless otherwise indicated.

“Alkynyl” refers to an unsaturated hydrocarbon group which may belinear, cyclic or branched or a combination thereof. Alkynyl groups with2-8 carbon atoms are preferred. The alkynyl group may contain 1, 2 or 3carbon-carbon triple bonds. Examples of alkynyl groups include ethynyl,n-propynyl, n-but-2-ynyl, n-hex-3-ynyl and the like. Alkynyl groups canbe substituted or unsubstituted, unless otherwise indicated.

“Aryl” refers to a polyunsaturated, aromatic hydrocarbon group having asingle ring (monocyclic) or multiple rings (bicyclic), which can befused together or linked covalently. Aryl groups with 6-10 carbon atomsare preferred, where this number of carbon atoms can be designated byC₆₋₁₀, for example. Examples of aryl groups include phenyl andnaphthalene-1-yl, naphthalene-2-yl, biphenyl and the like. Aryl groupscan be substituted or unsubstituted, unless otherwise indicated.

“Halo” or “halogen”, by itself or as part of a substituent refers to achlorine, bromine, iodine, or fluorine atom.

“Haloalkyl”, as a substituted alkyl group, refers to a monohaloalkyl orpolyhaloalkyl group, most typically substituted with from 1-3 halogenatoms. Examples include 1-chloroethyl, 3-bromopropyl, trifluoromethyland the like.

“Heterocyclyl” refers to a saturated or unsaturated non-aromatic ringcontaining at least one heteroatom (typically 1 to 5 heteroatoms)selected from nitrogen, oxygen or sulfur. The heterocyclyl ring may bemonocyclic or bicyclic. Preferably, these groups contain 0-5 nitrogenatoms, 0-2 sulfur atoms and 0-2 oxygen atoms. More preferably, thesegroups contain 0-3 nitrogen atoms, 0-1 sulfur atoms and 0-1 oxygenatoms. Examples of heterocycle groups include pyrrolidine, piperidine,imidazolidine, pyrazolidine, butyrolactam, valerolactam,imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine,1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide,thiomorpholine-S,S-dioxide, piperazine, pyran, pyridone, 3-pyrroline,thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidineand the like. Preferred heterocyclic groups are monocyclic, though theymay be fused or linked covalently to an aryl or heteroaryl ring system.

In one preferred embodiment, heterocyclic groups may be represented byformula (AA) below:

where formula (AA) is attached via a free valence on either M¹ or M²; M¹represents O, NR^(e), or S(O)_(l); M² represents CR^(f)R^(g), O,S(O)_(l), or NR^(e); l is 0, 1 or 2; j is 1, 2 or 3 and k is 1, 2 or 3,with the proviso that j+k is 3, 4, or 5; and R^(a), R^(b), R^(c), R^(d),R^(e), R^(f), and R^(g) are independently selected from the groupconsisting of hydrogen, halogen, unsubstituted or substituted C₁₋₈alkyl, unsubstituted or substituted C₂₋₈ alkenyl, unsubstituted orsubstituted C₂₋₈ alkynyl, —COR^(h), —CO₂R^(h), —CONR^(h)R^(i),—NR^(h)COR^(i), —SO₂R^(h), —SO₂NR^(h)R^(i), —NSO₂R^(h)R^(i)—NR^(h)R^(i),—OR^(h), -Q¹COR^(h), -Q¹CO₂R^(h), -Q¹CONR^(h)R^(i), -Q¹NR^(h)COR^(i),-Q¹SO₂R²⁸, -Q¹SO₂NR^(h)R^(i), -Q¹NSO₂R^(h)R^(i), -Q¹NR^(h)R^(i),-Q¹OR^(h) wherein Q¹ is a member selected from the group consisting ofC₁₋₄ alkylene, C₂₋₄ alkenylene and C₂₋₄ alkynylene, and R^(h) and R^(i)are independently selected from the group consisting of hydrogen andC₁₋₈ alkyl, and wherein the aliphatic portions of each of the R^(a),R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), R^(h) and R^(i) substituentsare optionally substituted with from one to three members selected fromthe group consisting of halogen, —OH, —OR^(n), —OC(O)NHR^(n),—OC(O)NR^(n)R^(o), —SH, —SR^(n), —S(O)R^(n), —S(O)₂R^(n), —SO₂NH₂,—S(O)₂NHR^(n), —S(O)₂NR^(n)R^(o), —NHS(O)₂R^(n), —NR^(n)S(O)₂R^(o),—C(O)NH₂, —C(O)NHR^(n), —C(O)NR^(n)R^(o), —C(O)R^(n), —NHC(O)R^(o),—NR^(n)C(O)R^(o), —NHC(O)NH₂, —NR^(n)C(O)NH₂, —NR^(n)C(O)NHR^(o),—NHC(O)NHR^(n), —NR^(n)C(O)NR^(o)R^(p), —NHC(O)NR^(n)R^(o), —CO₂H,—CO₂R^(n), —NHCO₂R^(n), —NR^(n)CO₂R^(o), —CN, —NO₂, —NH₂, —NHR^(n),—NR^(n)R^(o), —NR^(n)S(O)NH₂ and —NR^(n)S(O)₂NHR^(o), wherein R^(n),R^(o) and R^(p) are independently an unsubstituted C₁₋₈ alkyl.Additionally, any two of R^(a), R^(b), R^(c), R^(d), R^(f) and R^(g) maybe combined to form a bridged or spirocyclic ring system.

In one preferred embodiment, the number of R^(a)+R^(b)+R^(c)+R^(d)groups that are other than hydrogen is 0, 1 or 2. In a more preferredembodiment, R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), and R^(g) areindependently selected from the group consisting of hydrogen, halogen,unsubstituted or substituted C₁₋₈ alkyl, —COR^(h), —CO₂R^(h),—CONR^(h)R^(h), —NR^(h)COR^(h), —SO₂R^(h), —SO₂NR^(h)R^(i),—NSO₂R^(h)R^(i), —NR^(h)R^(i), and —OR^(h), wherein R^(h) and R^(i) areindependently selected from the group consisting of hydrogen andunsubstituted C₁₋₈ alkyl and wherein the aliphatic portions of each ofthe R^(a), R^(b), R^(c), R^(d), R^(e), R^(f) and R^(g) substituents areoptionally substituted with from one to three members selected from thegroup consisting of halogen, —OH, —OR^(n), —OC(O)NHR^(n),—OC(O)NR^(n)R^(o), —SH, —SR^(n), —S(O)R^(o), —S(O)₂R^(n), —SO₂NH₂,—S(O)₂NHR^(n), —S(O)₂NR^(n)R^(o), —NHS(O)₂R^(n), —NR^(n)S(O)₂R^(o),—C(O)NH₂, —C(O)NHR^(n), —C(O)NR^(n)R^(o), —C(O)R^(n), —NHC(O)R^(n),—NR^(n)C(O)R^(o), —NHC(O)NH₂, —NR^(n)C(O)NH₂, —NR^(n)C(O)NHR^(o),—NHC(O)NHR^(n), —NR^(n)C(O)NR^(o)R^(p), —NHC(O)NR^(n)R^(o), —CO₂H,—CO₂R^(n), —NHCO₂R^(n), —NR^(n)CO₂R^(o), —CN, —NO₂, —NH₂, —NHR^(n),—NR^(n)R^(o), —NR^(n)S(O)NH₂ and —NR^(n)S(O)₂NHR^(o), wherein R^(n),R^(o) and R^(p) are independently an unsubstituted C₁₋₈ alkyl.

In a more preferred embodiment, R^(a), R^(b), R^(c), R^(d), R^(e),R^(f), and R^(g) are independently hydrogen or C₁₋₄ alkyl. In anotherpreferred embodiment, at least three of R^(a), R^(b), R^(c), R^(d),R^(e), R^(f), and R^(g) are hydrogen.

“Heteroaryl” refers to an aromatic group containing at least oneheteroatom, where the heteroaryl group may be monocyclic or bicyclic.Examples include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl,triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl,phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl,benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl,benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl,imidazopyridines, benzothiazolyl, benzofuranyl, benzothienyl, indolyl,azaindolyl, azaindazolyl, quinolyl, isoquinolyl, isothiazolyl,pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, thiazolyl,furyl or thienyl. Preferred heteroaryl groups are those having at leastone aryl ring nitrogen atom, such as quinolinyl, quinoxalinyl, purinyl,benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzothiazolyl, indolyl,quinolyl, isoquinolyl and the like. Preferred 6-ring heteroaryl systemsinclude pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl and thelike. Preferred 5-ring heteroaryl systems include isothiazolyl,pyrazolyl, imidazolyl, thienyl, furyl, triazolyl, tetrazolyl, oxazolyl,isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, thiazolyl and the like.

Heterocyclyl and heteroaryl can be attached at any available ring carbonor heteroatom. Each heterocyclyl and heteroaryl may have one or morerings. When multiple rings are present, they can be fused together orlinked covalently. Each heterocyclyl and heteroaryl must contain atleast one heteroatom (typically 1 to 5 heteroatoms) selected fromnitrogen, oxygen or sulfur. Preferably, these groups contain 0-5nitrogen atoms, 0-2 sulfur atoms and 0-2 oxygen atoms. More preferably,these groups contain 0-3 nitrogen atoms, 0-1 sulfur atoms and 0-1 oxygenatoms. Heterocyclyl and heteroaryl groups can be substituted orunsubstituted, unless otherwise indicated. For substituted groups, thesubstitution may be on a carbon or heteroatom. For example, when thesubstitution is oxo (═O or —O⁻), the resulting group may have either acarbonyl (—C(O)—) or a N-oxide (—N⁺—O⁻).

Suitable substituents for substituted alkyl, substituted alkenyl, andsubstituted alkynyl include halogen, —CN, —CO₂R′, —C(O)R′, —C(O)NR′R″,oxo (═O or —O⁻), —OR′, —OC(O)R′, —OC(O)NR′R″—NO₂, —NR′C(O)R″,—NR″′C(O)NR′R″, —NR′R″, —NR′CO₂R″, —NR′S(O)R″, —NR′S(O)₂R′″,—NR″′S(O)NR′R″, —NR″′S(O)₂NR′R″, —SR′, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″,—NR′—C(NHR″)═NR′″, —SiR′R″R′″, —N₃, substituted or unsubstituted C₆₋₁₀aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, andsubstituted or unsubstituted 3- to 10-membered heterocyclyl. The numberof possible substituents range from zero to (2m′+1), where m′ is thetotal number of carbon atoms in such radical.

Suitable substituents for substituted aryl, substituted heteroaryl andsubstituted heterocyclyl include halogen, —CN, —CO₂R′, —C(O)R′,—C(O)NR′R″, oxo (═O or —O⁻), —OR′, —OC(O)R′, —OC(O)NR′R″, —NO₂,—NR′C(O)R″, —NR″′C(O)NR′R″, —NR′R″, —NR′CO₂R″, —NR′S(O)R″, —NR′S(O)₂R″,—NR″′S(O)NR′R″, —NR″′S(O)₂NR′R″, —SR′, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″,—NR′—C(NHR″)═NR′″, —SiR′R″R′″, —N₃, substituted or unsubstituted C₁₋₈alkyl, substituted or unsubstituted C₂₋₈ alkenyl, substituted orunsubstituted C₂₋₈ alkynyl, substituted or unsubstituted C₆₋₁₀ aryl,substituted or unsubstituted 5- to 10-membered heteroaryl, andsubstituted or unsubstituted 3- to 10 membered heterocyclyl. The numberof possible substituents range from zero to the total number of openvalences on the aromatic ring system.

As used above, R′, R″ and R′″ each independently refer to a variety ofgroups including hydrogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted C₂₋₈ alkenyl, substituted or unsubstitutedC₂₋₈ alkynyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted arylalkyl, substituted or unsubstitutedaryloxyalkyl. When R′ and R″ are attached to the same nitrogen atom,they can be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or7-membered ring (for example, —NR′R″ includes 1-pyrrolidinyl and4-morpholinyl). Furthermore, R′ and R″, R″ and R′″, or R′ and R′″ maytogether with the atom(s) to which they are attached, form a substitutedor unsubstituted 5-, 6- or 7-membered ring.

Two of the substituents on adjacent atoms of an aryl or heteroaryl ringmay optionally be replaced with a substituent of the formula-T-C(O)—(CH₂)_(q)—U—, wherein T and U are independently —NR″″—, —O—,—CH₂— or a single bond, and q is an integer of from 0 to 2.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula -A′-(CH₂)_(r)B′—, wherein A′ and B′ are independently —CH₂—,—O—, —NR″″—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR″″— or a single bond, and ris an integer of from 1 to 3. One of the single bonds of the new ring soformed may optionally be replaced with a double bond. Alternatively, twoof the substituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula—(CH₂)_(s)—X—(CH₂)_(t)—, where s and t are independently integers offrom 0 to 3, and XIV is —O—, —NR″″—, —S—, —S(O)—, —S(O)₂—, or—S(O)₂NR′—. R″″ in is selected from hydrogen or unsubstituted C₁₋₈alkyl.

“Heteroatom” is meant to include oxygen (O), nitrogen (N), sulfur (S)and silicon (Si).

“Pharmaceutically acceptable” carrier, diluent, or excipient is acarrier, diluent, or excipient compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof.

“Pharmaceutically-acceptable salt” refers to a salt which is acceptablefor administration to a patient, such as a mammal (e.g., salts havingacceptable mammalian safety for a given dosage regime). Such salts canbe derived from pharmaceutically-acceptable inorganic or organic basesand from pharmaceutically-acceptable inorganic or organic acids,depending on the particular substituents found on the compoundsdescribed herein. When compounds of the present invention containrelatively acidic functionalities, base addition salts can be obtainedby contacting the neutral form of such compounds with a sufficientamount of the desired base, either neat or in a suitable inert solvent.Salts derived from pharmaceutically-acceptable inorganic bases includealuminum, ammonium, calcium, copper, ferric, ferrous, lithium,magnesium, manganic, manganous, potassium, sodium, zinc and the like.Salts derived from pharmaceutically-acceptable organic bases includesalts of primary, secondary, tertiary and quaternary amines, includingsubstituted amines, cyclic amines, naturally-occurring amines and thelike, such as arginine, betaine, caffeine, choline,N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lysine, methylglucamine, morpholine,piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine, tromethamineand the like. When compounds of the present invention contain relativelybasic functionalities, acid addition salts can be obtained by contactingthe neutral form of such compounds with a sufficient amount of thedesired acid, either neat or in a suitable inert solvent. Salts derivedfrom pharmaceutically-acceptable acids include acetic, ascorbic,benzenesulfonic, benzoic, camphosulfonic, citric, ethanesulfonic,fumaric, gluconic, glucoronic, glutamic, hippuric, hydrobromic,hydrochloric, isethionic, lactic, lactobionic, maleic, malic, mandelic,methanesulfonic, mucic, naphthalenesulfonic, nicotinic, nitric, pamoic,pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonicand the like.

Also included are salts of amino acids such as arginate and the like,and salts of organic acids like glucuronic or galactunoric acids and thelike (see, for example, Berge, S. M. et al, “Pharmaceutical Salts”, J.Pharmaceutical Science, 1977, 66:1-19). Certain specific compounds ofthe present invention contain both basic and acidic functionalities thatallow the compounds to be converted into either base or acid additionsalts.

The neutral forms of the compounds may be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the present invention.

“Salt thereof” refers to a compound formed when the hydrogen of an acidis replaced by a cation, such as a metal cation or an organic cation andthe like. Preferably, the salt is a pharmaceutically-acceptable salt,although this is not required for salts of intermediate compounds whichare not intended for administration to a patient.

In addition to salt forms, the present invention provides compoundswhich are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

Prodrugs may be prepared by modifying functional groups present in thecompounds in such a way that the modifications are cleaved, either inroutine manipulation or in vivo, to the parent compounds. Prodrugsinclude compounds wherein hydroxyl, amino, sulfhydryl, or carboxylgroups are bonded to any group that, when administered to a mammaliansubject, cleaves to form a free hydroxyl, amino, sulfhydryl, or carboxylgroup respectively. Examples of prodrugs include, but are not limitedto, acetate, formate and benzoate derivatives of alcohol and aminefunctional groups in the compounds of the invention. Preparation,selection, and use of prodrugs is discussed in T. Higuchi and V. Stella,“Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. SymposiumSeries; “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985; and inBioreversible Carriers in Drug Design, ed. Edward B. Roche, AmericanPharmaceutical Association and Pergamon Press, 1987, each of which arehereby incorporated by reference in their entirety.

The compounds of the invention may be present in the form ofpharmaceutically acceptable metabolites thereof. The term “metabolite”means a pharmaceutically acceptable form of a metabolic derivative of acompound of the invention (or a salt thereof). In some aspects, themetabolite may be a functional derivative of a compound that is readilyconvertible in vivo into an active compound. In other aspects, themetabolite may be an active compound.

“Therapeutically effective amount” refers to an amount sufficient toeffect treatment when administered to a patient in need of treatment.

“Treating” or “treatment” as used herein refers to the treating ortreatment of a disease or medical condition (such as a viral, bacterialor fungal infection or other infectious diseases, as well as autoimmuneor inflammatory conditions) in a patient, such as a mammal (particularlya human or a companion animal) which includes ameliorating the diseaseor medical condition, i.e., eliminating or causing regression of thedisease or medical condition in a patient; suppressing the disease ormedical condition, i.e., slowing or arresting the development of thedisease or medical condition in a patient; or alleviating the symptomsof the disease or medical condition in a patient.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, bothsolvated forms and unsolvated forms are intended to be encompassedwithin the scope of the present invention. Certain compounds of thepresent invention may exist in multiple crystalline or amorphous forms(i.e., as polymorphs). In general, all physical forms are equivalent forthe uses contemplated by the present invention and are intended to bewithin the scope of the present invention.

It will be apparent to one skilled in the art that certain compounds ofthe present invention may exist in tautomeric forms, all such tautomericforms of the compounds being within the scope of the invention. Certaincompounds of the present invention possess asymmetric carbon atoms(optical centers) or double bonds; the racemates, diastereomers,geometric isomers and individual isomers (e.g., separate enantiomers)are all intended to be encompassed within the scope of the presentinvention. The compounds of the present invention may also containunnatural proportions of atomic isotopes at one or more of the atomsthat constitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areintended to be encompassed within the scope of the present invention.

The compounds of the present invention may include a detectable label. Adetectable label is a group that is detectable at low concentrations,usually less than micromolar, possibly less than nanomolar, and that canbe readily distinguished from other molecules, due to differences in amolecular property (e.g. molecular weight, mass to charge ratio,radioactivity, redox potential, luminescence, fluorescence,electromagnetic properties, binding properties, and the like).Detectable labels may be detected by spectroscopic, photochemical,biochemical, immunochemical, electrical, magnetic, electromagnetic,optical or chemical means and the like.

A wide variety of detectable labels are within the scope of the presentinvention, including hapten labels (e.g. biotin, or labels used inconjunction with detectable antibodies such as horse radish peroxidaseantibodies); mass tag labels (e.g. stable isotope labels); radioisotopiclabels (including ³H, ¹²⁵I, ³⁵S, ¹⁴C, or ³²P); metal chelate labels;luminescent labels including fluorescent labels (such as fluorescein,isothiocyanate, Texas red, rhodamine, green fluorescent protein, and thelike), phosphorescent labels, and chemiluminescent labels, typicallyhaving quantum yield greater than 0.1; electroactive and electrontransfer labels; enzyme modulator labels including coenzymes,organometallic catalysts horse radish peroxidase, alkaline phosphataseand others commonly used in an ELISA; photosensitizer labels; magneticbead labels including Dynabeads; calorimetric labels such as colloidalgold, silver, selenium, or other metals and metal sol labels (see U.S.Pat. No. 5,120,643, which is herein incorporated by reference in itsentirety for all purposes), or colored glass or plastic (e.g.,polystyrene, polypropylene, latex, etc.) bead labels; and carbon blacklabels. Patents teaching the use of such detectable labels include U.S.Pat. Nos. 3,817,837; 3,850,752; 3,939,350; 3,996,345; 4,277,437;4,275,149; 4,366,241; 6,312,914; 5,990,479; 6,207,392; 6,423,551;6,251,303; 6,306,610; 6,322,901; 6,319,426; 6,326,144; and 6,444,143,which are herein incorporated by reference in their entirety for allpurposes.

Detectable labels are commercially available or may be prepared as knownto one skilled in the art. Detectable labels may be covalently attachedto the compounds using a reactive functional group, which can be locatedat any appropriate position. Methods for attaching a detectable labelare known to one skilled in the art. When the reactive group is attachedto an alkyl, or substituted alkyl chain tethered to an aryl nucleus, thereactive group may be located at a terminal position of an alkyl chain.

Compounds

The present invention provides compounds that modulate at least one ofCCR9 activity. Chemokine receptors are integral membrane proteins whichinteract with an extracellular ligand, such as a chemokine, and mediatea cellular response to the ligand, e.g., chemotaxis, increasedintracellular calcium ion concentration, etc. Therefore, modulation of achemokine receptor function, e.g., interference with a chemokinereceptor ligand interaction, will modulate a chemokine receptor mediatedresponse, and treat or prevent a chemokine receptor mediated conditionor disease. Modulation of a chemokine receptor function includes bothinducement and inhibition of the function. The type of modulationaccomplished will depend on the characteristics of the compound, i.e.,antagonist or full, partial or inverse agonist.

For example, compounds of this invention act as potent CCR9 antagonists,and this antagonistic activity has been further confirmed in animaltesting for inflammation, one of the hallmark disease states for CCR9.Accordingly, the compounds provided herein are useful in pharmaceuticalcompositions, methods for the treatment of CCR9-mediated diseases, andas controls in assays for the identification of competitive CCR9antagonists.

In the formulae set forth below, when a variable appears more than oncein the same formula, it can be either the same or different. Forexample, in formula (II), one R⁴ can be halogen and the remainder can behydrogen.

In one embodiment, the compounds of the present invention arerepresented by formula (I), or salts thereof:

where Ar¹ is a substituted or unsubstituted C₆₋₁₀ aryl or substituted orunsubstituted 5- to 10-membered heteroaryl; each having 0 to 5substituents selected from the group consisting of halogen, substitutedor unsubstituted C₁₋₈ alkyl, substituted or unsubstituted C₂₋₈ alkenyl,substituted or unsubstituted C₂₋₈ alkynyl, —CN, —NO₂, ═O, —C(O)R³,—CO₂R³, —C(O)NR³R⁴, —OR³, —OC(O)R³, —OC(O)NR³R⁴, —NR⁵C(O)R³,—NR⁵C(O)NR³R⁴, —NR³R⁴, —NR⁵CO₂R³, —NR⁵S(O)₂R³, —SR³, —S(O)R³, —S(O)₂R³,—S(O)₂NR³R⁴, substituted or unsubstituted C₆₋₁₀ aryl, substituted orunsubstituted 5- to 10-membered heteroaryl, and substituted orunsubstituted 3- to 10-membered heterocyclyl;

A is N or CR⁴;

X¹

X²

X³ are selected from the group consisting of:

-   -   N—N═N,    -   C═N—N(R⁵),    -   N—C(R⁶)═N,    -   N—N═C(R⁷),    -   N—C(R⁶)═C(R⁷),    -   C═N—C(R⁷), and    -   C═C(R⁶)—N(R⁵); (such that         is either a single bond or double bond);

R¹ is hydrogen or C₁₋₈ alkyl;

each R², R³, R⁴, R⁶ and R⁷, when present, are independently selectedfrom the group consisting of hydrogen, halogen, substituted orunsubstituted C₁₋₈ alkyl, substituted or unsubstituted C₂₋₈ alkenyl,substituted or unsubstituted C₂₋₈ alkynyl, —CN, ═O, —NO₂, —OR′,—OC(O)R′, —CO₂R′, —C(O)R′, —C(O)NR″R′, —OC(O)NR″R′, —NR″′C(O)R′,—NR″′C(O)NR″R′, —NR″R′, —NR″′CO₂R′, —SR′, —S(O)R′, —S(O)₂R′,—S(O)₂NR″R′, —NR″S(O)₂R′, substituted or unsubstituted C₆₋₁₀ aryl,substituted or unsubstituted 5- to 10-membered heteroaryl andsubstituted or unsubstituted 3- to 10-membered heterocyclyl; or

R² and R³ together with the atoms which they substitute form asubstituted or unsubstituted 5-, 6-, or 7-membered ring;

each R⁵ is independently selected from group consisting of hydrogen,substituted or unsubstituted C₁₋₈ alkyl, substituted or unsubstitutedC₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkynyl, —CO₂R′,—C(O)R′, —C(O)NR″R′, —S(O)R′, —S(O)₂R′, —S(O)₂NR″R′, substituted orunsubstituted C₆₋₁₀ aryl, substituted or unsubstituted 5- to 10-memberedheteroaryl, and substituted or unsubstituted 3- to 10-memberedheterocyclyl; and

R′, R″ and R′″ are each independently hydrogen or unsubstituted C₁₋₄alkyl; or R′ and R″ together with the atoms which they substitute form asubstituted or unsubstituted 5-, 6-, or 7-membered ring.

In one embodiment of the present invention, each R², R³, R⁴, R⁶ and R⁷,when present, are independently selected from the group consisting ofhydrogen, halogen, substituted or unsubstituted C₁₋₈ alkyl, substitutedor unsubstituted C₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈alkynyl, —CN, —NO₂, —OR′, —OC(O)R′, —CO₂R′, —C(O)R′, —C(O)NR″R′,—OC(O)NR″R′, —NR″′C(O)R′, —NR″′C(O)NR″R′, —NR″R′, —NR″′CO₂R′, —SR′,—S(O)R′, —S(O)₂R′, —S(O)₂NR″R′, —NR″S(O)₂R′, substituted orunsubstituted C₆₋₁₀ aryl, substituted or unsubstituted 5- to 10-memberedheteroaryl and substituted or unsubstituted 3- to 10-memberedheterocyclyl.

In one embodiment, a compound of the present invention is selected fromthe group consisting of:

-   4-tert-butyl-N-(4-chloro-2-(1H-pyrazolo[3,4-b]pyridin-3-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide;-   N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chloro-5-fluorophenyl)-4-tert-butylbenzenesulfonamide;-   1-(2-(4-tert-butylphenylsulfonamido)-4-chlorophenyl)-N,N-dimethyl-1H-pyrazole-4-carboxamide;-   4-tert-butyl-N-(4-chloro-2-(1H-pyrazol-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(4-chloro-1H-pyrazol-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide;-   ethyl    1-(2-(4-tert-butylphenylsulfonamido)-5-chlorophenyl)-1H-pyrazole-4-carboxylate;-   4-tert-butyl-N-(4-chloro-2-(4-isopropyl-1H-pyrazol-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(2-methyl-1H-imidazol-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(2-isopropyl-1H-imidazol-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(1H-indol-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(1H-imidazo[4,5-b]pyridin-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(1H-indazol-1-yl)phenyl)benzenesulfonamide;-   N-(2-(1H-benzo[d][1,2,3]triazol-1-yl)-4-chlorophenyl)-4-tert-butylbenzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(9H-purin-9-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(7H-purin-7-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(2-ethyl-1H-imidazol-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(2,4-dimethyl-1H-imidazol-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(2-ethyl-4-methyl-1H-imidazol-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(1H-imidazo[4,5-b]pyridin-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(3H-imidazo[4,5-b]pyridin-3-yl)phenyl)benzenesulfonamide;-   N-(2-(2-amino-7H-purin-7-yl)-4-chlorophenyl)-4-tert-butylbenzenesulfonamide;-   N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-tert-butylbenzenesulfonamide;-   N-(2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-4-chlorophenyl)-4-tert-butylbenzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(2-methyl-1H-benzo[d]imidazol-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(1H-imidazo[4,5-c]pyridin-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(3H-imidazo[4,5-c]pyridin-3-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(2-oxo-1H-imidazo[4,5-c]pyridin-3(2H)-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(1H-pyrrolo[3,2-c]pyridin-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(1H-pyrrolo[3,2-b]pyridin-1-yl)phenyl)benzenesulfonamide;-   1-(2-(4-tert-butylphenylsulfonamido)-5-chlorophenyl)-N,N-dimethyl-1H-pyrazole-4-carboxamide;-   1-(2-(4-tert-butylphenylsulfonamido)-5-chlorophenyl)-1H-pyrazole-4-carboxamide;-   N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-isopropoxybenzenesulfonamide;-   N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-(4-methyltetrahydro-2H-pyran-4-yl)benzenesulfonamide;-   N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-tert-pentylbenzenesulfonamide;    and-   N-(2-(2-amino-9H-purin-9-yl)-4-chlorophenyl)-4-tert-butylbenzenesulfonamide;    or a salt thereof.

In one embodiment, a compound of the present invention is selected fromthe group consisting of:

-   N-(2-(6-amino-9H-purin-9-yl)-4-chlorophenyl)-4-tert-butylbenzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide;-   ethyl    1-(2-(4-tert-butylphenylsulfonamido)-5-chlorophenyl)-1H-1,2,3-triazole-4-carboxylate;-   N-(2-(5-amino-1H-pyrrolo[3,2-b]pyridine-1-yl)-4-chlorophenyl)-4-tert-butylbenzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(5-methyl-1H-[1,2,3]triazolo[4,5-b]pyridine-1-yl)phenyl)benzenesulfonamide;-   N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridine-1-yl)-4-chlorophenyl)-4-isopropylbenzenesulfonamide;-   N-(2-(5-amino-1H-[1,2,3]triazolo[4,5-b]pyridine-1-yl)-4-chlorophenyl)-4-tert-butylbenzenesulfonamide;-   1-(2-(4-tert-butylphenylsulfonamido)-5-chlorophenyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide;-   1-(2-(4-tert-butylphenylsulfonamido)-5-chlorophenyl)-N,N-dimethyl-1H-1,2,3-triazole-4-carboxamide;-   N-(2-(4-(azetidine-1-carbonyl)-1H-1,2,3-triazol-1-yl)-4-chlorophenyl)-4-tert-butylbenzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(4-(4-methylpiperazine-1-carbonyl)-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide;-   1-(2-(4-tert-butylphenylsulfonamido)-5-chlorophenyl)-1H-1,2,3-triazole-4-carboxamide;-   1-(2-(4-tert-butylphenylsulfonamido)-5-chlorophenyl)-1H-1,2,3-triazole-4-carboxylic    acid;-   4-tert-butyl-N-(4-chloro-2-(4-(dimethylamino)-1H-pyrazolo[4,3-c]pyridine-1-yl)phenyl)benzenesulfonamide;-   N-(2-(4-amino-1H-[1,2,3]triazolo[4,5-c]pyridine-1-yl)-4-chlorophenyl)-4-tert-butylbenzenesulfonamide;-   N-(2-(4-amino-1H-pyrazolo[4,3-c]pyridine-1-yl)-4-chlorophenyl)-4-tert-butylbenzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridine-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(4-morpholino-1H-[1,2,3]triazolo[4,5-c]pyridine-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-morpholino-2-(4-morpholino-1H-[1,2,3]triazolo[4,5-c]pyridine-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(3,4-dichloro-2-(1H-pyrazol-1-yl)phenyl)benzenesulfonamide;-   N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridine-1-yl)-4-cyanophenyl)-4-tert-butylbenzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(5-methyl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-b]pyridine-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-b]pyridine-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(4-(2-methoxyethyl)-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-b]pyridine-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(4-methyl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-b]pyridine-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(4-ethyl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-b]pyridine-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(4-isopropyl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-b]pyridine-1-yl)phenyl)benzenesulfonamide;-   N-(2-(4-acetyl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-b]pyridine-1-yl)-4-chlorophenyl)-4-tert-butylbenzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(4-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-b]pyridine-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(5-isopropyl-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(5-ethyl-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(5-(morpholinomethyl)-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(4-((dimethylamino)methyl)-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(5-(pyrrolidin-1-ylmethyl)-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide;-   N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridine-1-yl)-4-chlorophenyl)-3-fluoro-4-morpholinobenzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(4-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(5-chloro-2-(1H-pyrazolo[4,3-b]pyridine-1-yl)pyridine-3-yl)benzenesulfonamide;-   4-tert-butyl-N-(5-chloro-2-(5-methyl-1H-pyrazolo[4,3-b]pyridine-1-yl)pyridine-3-yl)benzenesulfonamide;-   4-tert-butyl-N-(5-chloro-2-(1H-imidazo[4,5-b]pyridine-1-yl)pyridine-3-yl)benzenesulfonamide;    and-   4-tert-butyl-N-(5-chloro-2-(3H-imidazo[4,5-b]pyridine-3-yl)pyridine-3-yl)benzenesulfonamide;

or a salt thereof.

In one embodiment, a compound of the present invention is selected fromthe group consisting of:

-   N-(2-(5-amino-1H-pyrrolo[3,2-b]pyridin-1-yl)-5-chloropyridin-3-yl)-4-tert-butylbenzenesulfonamide;-   N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-5-chloropyridin-3-yl)-4-tert-butylbenzenesulfonamide;-   ethyl    1-(3-(4-tert-butylphenylsulfonamido)-5-chloropyridin-2-yl)-1H-pyrazole-4-carboxylate;-   N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-5-methylpyridin-3-yl)-4-tert-butylbenzenesulfonamide;-   4-tert-butyl-N-(5-chloro-2-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)benzenesulfonamide;-   4-tert-butyl-N-(5-chloro-2-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl)benzenesulfonamide;-   4-tert-butyl-N-(5-chloro-2-(4-phenyl-1H-imidazol-1-yl)pyridin-3-yl)benzenesulfonamide;-   4-tert-butyl-N-(5-chloro-2-(2-methyl-1H-imidazol-1-yl)pyridin-3-yl)benzenesulfonamide;-   4-tert-butyl-N-(5-chloro-2-(2-isopropyl-1H-imidazol-1-yl)pyridin-3-yl)benzenesulfonamide;-   4-tert-butyl-N-(5-chloro-2-(2-phenyl-1H-imidazol-1-yl)pyridin-3-yl)benzenesulfonamide;-   4-tert-butyl-N-(5-chloro-2-(2-ethyl-1H-imidazol-1-yl)pyridin-3-yl)benzenesulfonamide;-   4-tert-butyl-N-(5-chloro-2-(1H-indol-1-yl)pyridin-3-yl)benzenesulfonamide;-   N-(2-(1H-benzo[d]imidazol-1-yl)-5-chloropyridin-3-yl)-4-tert-butylbenzenesulfonamide;-   4-tert-butyl-N-(5-chloro-2-(1H-indazol-1-yl)pyridin-3-yl)benzenesulfonamide;-   N-(2-(1H-benzo[d][1,2,3]triazol-1-yl)-5-chloropyridin-3-yl)-4-tert-butylbenzenesulfonamide;-   4-tert-butyl-N-(5-chloro-2-(9H-purin-9-yl)pyridin-3-yl)benzenesulfonamide;-   4-tert-butyl-N-(5-chloro-2-(2,4-dimethyl-1H-imidazol-1-yl)pyridin-3-yl)benzenesulfonamide;-   4-tert-butyl-N-(5-chloro-2-(2-ethyl-4-methyl-1H-imidazol-1-yl)pyridin-3-yl)benzenesulfonamide;-   4-tert-butyl-N-(5-chloro-2-(4-(piperidine-1-carbonyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzenesulfonamide;-   4-tert-butyl-N-(5-chloro-2-(4-(morpholine-4-carbonyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzenesulfonamide;-   4-tert-butyl-N-(5-chloro-2-(4-(pyrrolidine-1-carbonyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzenesulfonamide;-   4-tert-butyl-N-(5-chloro-2-(4-(4-methylpiperazine-1-carbonyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzenesulfonamide;-   N-(2-(4-(azetidine-1-carbonyl)-1H-pyrazol-1-yl)-5-chloropyridin-3-yl)-4-tert-butylbenzenesulfonamide;-   1-(3-(4-tert-butylphenylsulfonamido)-5-chloropyridin-2-yl)-N-isopropyl-N-methyl-1H-pyrazole-4-carboxamide;-   4-tert-butyl-N-(5-chloro-2-(4-(4-isopropylpiperazine-1-carbonyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzenesulfonamide;-   4-tert-butyl-N-(5-chloro-2-(4-(3-(dimethylamino)pyrrolidine-1-carbonyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzenesulfonamide;-   1-(3-(4-tert-butylphenylsulfonamido)-5-chloropyridin-2-yl)-N-(2-(dimethylamino)ethyl)-N-methyl-1H-pyrazole-4-carboxamide;-   4-tert-butyl-N-(5-chloro-2-(4-(1,2,3,6-tetrahydropyridine-1-carbonyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzenesulfonamide;-   1-(3-(4-tert-butylphenylsulfonamido)-5-chloropyridin-2-yl)-N-methyl-1H-pyrazole-4-carboxamide;-   1-(3-(4-tert-butylphenylsulfonamido)-5-chloropyridin-2-yl)-N,N-dimethyl-1H-pyrazole-4-carboxamide;-   1-(3-(4-tert-butylphenylsulfonamido)-5-chloropyridin-2-yl)-N,3-dimethyl-1H-pyrazole-4-carboxamide;-   1-(3-(4-tert-butylphenylsulfonamido)-5-chloropyridin-2-yl)-N,N,3-trimethyl-1H-pyrazole-4-carboxamide;-   1-(3-(4-tert-butylphenylsulfonamido)-5-chloropyridin-2-yl)-1H-pyrazole-4-carboxylic    acid;-   N-(2-(4-amino-1H-pyrazol-1-yl)-5-chloropyridin-3-yl)-4-tert-butylbenzenesulfonamide;-   N-(1-(3-(4-tert-butylphenylsulfonamido)-5-chloropyridin-2-yl)-1H-pyrazol-4-yl)acetamide;-   4-tert-butyl-N-(5-chloro-2-(4-(oxazol-2-yl)-1H-pyrazol-1-yl)pyridin-3-yl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(1H-indazol-3-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)benzenesulfonamide;-   N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-acetylbenzenesulfonamide;    and-   N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-(1-(hydroxyimino)ethyl)benzenesulfonamide;

or a salt thereof.

In one embodiment, a compound of the present invention is selected fromthe group consisting of:

-   N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-(1-(methoxyimino)ethyl)benzenesulfonamide;-   N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-(1-aminoethyl)benzenesulfonamide;-   N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-(1-(methylamino)ethyl)benzenesulfonamide;-   N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-(1-(dimethylamino)ethyl)benzenesulfonamide;-   N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-(1-morpholinoethyl)benzenesulfonamide;-   N-(4-Chloro-2[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-4-(1-hydroxy-1-methyl-ethyl)-benzene-sulfonamide;-   N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-(1-(ethoxyimino)ethyl)benzenesulfonamide;-   N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-(1-(allyloxyimino)ethyl)benzenesulfonamide;-   N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-(1-(tert-butoxyimino)ethyl)benzenesulfonamide;-   2-(1-(4-(N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)sulfamoyl)phenyl)ethylideneaminooxy)acetic    acid;-   N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-(1-hydroxy-2-methylpropan-2-yl)benzenesulfonamide;-   methyl    2-(4-(N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)sulfamoyl)phenyl)-2-methylpropanoate;-   N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-isopropylbenzenesulfonamide;-   N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-cyanobenzenesulfonamide;-   N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-(1-hydroxyethyl)benzenesulfonamide;-   N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzenesulfonamide;-   N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-(2-hydroxybutan-2-yl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(5-methyl-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(4-(1-hydroxyethyl)-5-methyl-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide;-   N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-iodobenzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(4-ethynyl-5-methyl-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(4-ethyl-5-methyl-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide;-   methyl    1-(2-(4-tert-butylphenylsulfonamido)-5-chlorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylate;-   4-tert-butyl-N-(4-chloro-2-(5-methyl-4-((methylamino)methyl)-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(4-((isopropylamino)methyl)-5-methyl-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(4-((cyclopropylamino)methyl)-5-methyl-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(4-((dimethylamino)methyl)-5-methyl-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(5-methyl-4-(morpholinomethyl)-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(5-methyl-4-(thiazol-2-yl)-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide;-   1-(2-(4-tert-butylphenylsulfonamido)-5-chlorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic    acid;-   4-tert-butyl-N-(4-chloro-2-(5-methyl-4-(oxazol-2-yl)-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(4-(hydroxymethyl)-1H-pyrazol-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(4-((isopropylamino)methyl)-1H-pyrazol-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(4-((methylamino)methyl)-1H-pyrazol-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(4-(morpholinomethyl)-1H-pyrazol-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(4-((dimethylamino)methyl)-1H-pyrazol-1-yl)phenyl)benzenesulfonamide;-   ethyl    1-(2-(4-tert-butylphenylsulfonamido)-5-chlorophenyl)-5-methyl-1H-pyrazole-4-carboxylate;-   4-tert-butyl-N-(4-chloro-2-(4-(2-hydroxypropan-2-yl)-5-methyl-1H-pyrazol-1-yl)phenyl)benzenesulfonamide;-   N-(4-Chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-3-fluoro-4-(1-hydroxy-1-methyl-ethyl)-benzenesulfonamide;-   N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-(2-hydroxypropan-2-yl)-3-methylbenzenesulfonamide;-   N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-3-chloro-4-(2-hydroxypropan-2-yl)benzenesulfonamide;-   N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-(2-hydroxypropan-2-yl)-3-methoxybenzenesulfonamide;    and-   N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-(2-hydroxypropan-2-yl)-3-(trifluoromethyl)benzenesulfonamide;

or a salt thereof.

In one embodiment, a compound of the present invention is selected fromthe group consisting of:

-   4-tert-butyl-N-(4-chloro-2-(4-(2-hydroxypropan-2-yl)-5-methyl-1H-pyrazol-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(4-ethynyl-5-methyl-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide;-   N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-isopropylbenzenesulfonamide;-   N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-(1-(hydroxyimino)ethyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(5-methyl-4-(thiazol-2-yl)-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide;-   4-tert-butyl-N-(4-chloro-2-(4-(1-hydroxyethyl)-5-methyl-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide;-   N-(4-Chloro-2[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-4-(1-hydroxy-1-methyl-ethyl)-benzene-sulfonamide    sodium salt-   N-(4-Chloro-2[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-4-(1-hydroxy-1-methyl-ethyl)-benzene-sulfonamide;-   N-(4-Chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-3-fluoro-4-(1-hydroxy-1-methyl-ethyl)-benzenesulfonamide    sodium salt; and-   N-(4-Chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-3-fluoro-4-(1-hydroxy-1-methyl-ethyl)-benzenesulfonamide.

In one embodiment, the compounds of the present invention arerepresented by formula (II), or salts thereof:

where R⁸, R⁹, R¹⁰, R¹¹, and R¹² are each independently selected from thegroup consisting of hydrogen, halogen, C₁₋₈ alkoxy, C₁₋₈ alkyl, —CN, orC₁₋₈ haloalkyl, wherein R², R³, R⁴, X¹, X², and X³ are as defined abovein Formula I.

In one embodiment, the compounds of the present invention arerepresented by formula (III), or salts thereof:

where R⁸, R⁹, R¹⁰, R¹¹, and R¹² are as defined for formula (II).

In one embodiment, the compounds of the present invention arerepresented by formula (IV), or salts thereof:

where R⁸, R⁹, R¹⁰, R¹¹, and R¹² are as defined for formula (II).

In one embodiment, the compound is of the formula (V):

where R⁴, R⁵, R⁸, R⁹, R¹⁰, R¹¹, R¹², and X¹ and A are as defined informula (II).

In one embodiment, the compound is of the formula (VI):

where R⁴, R⁸, R⁹, and A are as defined in formula (II).

In one embodiment, the compound is of the formula (VII):

where R⁴, R⁸, and R⁹ are as defined in formula (II).

In one embodiment, the compound is of the formula (VIII):

where R⁴, R⁸, and R⁹ are as defined in formula (II).

In another embodiment, the compounds of the present invention are of theformula (CI):

where R¹ is halogen, C₁₋₈ alkoxy, C₁₋₈ alkyl, —CN, or C₁₋₈ haloalkyl;

each R² is independently hydrogen, halogen, C₁₋₈ alkyl, —CN, or C₁₋₈haloalkyl;

R³ is hydrogen or C₁₋₈ alkyl;

R⁴ is hydrogen, halogen or C₁₋₈ alkyl;

R⁵ is halogen, —CN or C₁₋₈ alkyl;

R⁶, R⁷, R⁸ and R⁹ are each independently selected from the groupconsisting of hydrogen, halogen, substituted or unsubstituted C₁₋₈alkyl, substituted or unsubstituted C₂₋₈ alkenyl, substituted orunsubstituted C₂₋₈ alkynyl, —CN, ═O, —NO₂, —OR′, —OC(O)R′, —CO₂R′,—C(O)R′, —C(O)NR″R′, —OC(O)NR″R′, —NR″′C(O)R′, —NR″′C(O)NR″R′, —NR″R′,—NR″′CO₂R′, —SR′, —S(O)R′, —S(O)₂R′, —S(O)₂NR″R′, —NR″S(O)₂R′,substituted or unsubstituted C₆₋₁₀ aryl, substituted or unsubstituted 5-to 10-membered heteroaryl and substituted or unsubstituted 3- to10-membered heterocyclyl; or

R⁶ and R⁷ together with the atoms which they substitute form asubstituted or unsubstituted 5-, 6-, or 7-membered ring;

R′, R″ and R′″ are each independently hydrogen or unsubstituted C₁₋₄alkyl; or R′ and R″ together with the atoms which they substitute form asubstituted or unsubstituted 5-, 6-, or 7-membered ring;

X¹ is CR⁸ or N; and

X² is CR⁹ or N.

In one embodiment, for the compounds of the present invention of theformula (CI), R⁶, R⁷, R⁸ and R⁹ are each independently selected from thegroup consisting of hydrogen, halogen, substituted or unsubstituted C₁₋₈alkyl, substituted or unsubstituted C₂₋₈ alkenyl, substituted orunsubstituted C₂₋₈ alkynyl, —CN, —NO₂, —OR′, —OC(O)R′, —CO₂R′, —C(O)R′,—C(O)NR″R′, —OC(O)NR″R′, —NR″′C(O)R′, —NR″′C(O)NR″R′, —NR″R′,—NR″′CO₂R′, —SR′, —S(O)R′, —S(O)₂R′, —S(O)₂NR″R′, —NR″S(O)₂R′,substituted or unsubstituted C₆₋₁₀ aryl, substituted or unsubstituted 5-to 10-membered heteroaryl and substituted or unsubstituted 3- to10-membered heterocyclyl.

In another embodiment, the compounds of the present invention are of theformula (CII):

where R¹, R⁵, R⁶, R⁷, X¹ and X² are as described in formula (I).

In another embodiment, the compounds of the present invention are of theformula (CIII):

where R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ are as described in formula(CI).

In another embodiment, the compounds of the present invention are of theformula (CIV):

where R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ are as described in formula(CI).

In another embodiment, the compounds of the present invention are of theformula (CV):

where R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ are as described in formula(CI).

In another embodiment, the compounds of the present invention are of theformula (CVI):

where R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ are as described in formula(CI).

In another embodiment, the compounds of the present invention are of theof the formula (CVII):

where R¹ and R⁵ are as described in formula (CI).

In another embodiment, the compounds of the present invention are of theformula (CCI):

where R¹ is halogen, C₁₋₈ alkoxy, C₁₋₈ alkyl, —CN, or C₁₋₈ haloalkyl;

each R² is independently hydrogen, halogen, C₁₋₈ alkyl, —CN, or C₁₋₈haloalkyl;

R³ is hydrogen or C₁₋₈ alkyl;

R⁴ is halogen or C₁₋₈ alkyl;

R⁵ is hydrogen, halogen or C₁₋₈ alkyl;

R⁶, R⁷, R⁸ and R⁹ are each independently selected from the groupconsisting of hydrogen, halogen, substituted or unsubstituted C₁₋₈alkyl, substituted or unsubstituted C₂₋₈ alkenyl, substituted orunsubstituted C₂₋₈ alkynyl, —CN, ═O, —NO₂, —OR′, —OC(O)R′, —CO₂R′,—C(O)R′, —C(O)NR″R′, —OC(O)NR″R′, —NR″′C(O)R′, —NR″′C(O)NR″R′, —NR″R′,—NR″′CO₂R′, —SR′, —S(O)R′, —S(O)₂R′, —S(O)₂NR″R′, —NR″S(O)₂R′,substituted or unsubstituted C₆₋₁₀ aryl, substituted or unsubstituted 5-to 10-membered heteroaryl and substituted or unsubstituted 3- to10-membered heterocyclyl; or

R⁶ and R⁷ together with the atoms which they substitute form ansubstituted or unsubstituted 5-, 6-, or 7-membered ring;

R′, R″ and R′″ are each independently hydrogen or unsubstituted C1-4alkyl; or R′ and R″ together with the atoms which they substitute form asubstituted or unsubstituted 5-, 6-, or 7-membered ring;

X¹ is CR⁸ or N; and

X² is CR⁹ or N.

In another embodiment, the compounds of the present invention are of theformula (CCII):

where R¹, R⁵, R⁶, R⁷, X¹ and X² are as defined in formula (CCI).

In another embodiment, the compounds of the present invention are of theformula (CCIII):

where R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ are as defined in formula(CCI).

In another embodiment, the compounds of the present invention are of theformula (CCIV):

where R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁹ are as defined in formula(CCI).

In another embodiment, the compounds of the present invention are of theformula (CCV):

where R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are as defined in formula(CCI).

In another embodiment, the compounds of the present invention are of theformula (CCVI):

where R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ are as defined in formula (CCI).

In the following preferred embodiments, the variables are defined whenpresent. For example, for preferred embodiments I-IV, Ar is only informula (I); whereas R⁸ is only present in formula (I-IV).

Known Compounds

The compounds shown below:

also referred to as:

-   2-Thiophenesulfonamide,    5-(5-isoxazolyl)-N-[5-methyl-2-(1H-pyrrol-1-yl)phenyl];-   Benzenesulfonamide,    N-[2-(1H-pyrrol-1-yl)-5-(trifluoromethyl)phenyl];-   Benzenesulfonamide,    4-methyl-N-[2-(1H-pyrrol-1-yl)-5-(trifluoromethyl)phenyl];-   3-Pyridinesulfonamide,    5-bromo-6-chloro-N-[2-(1H-pyrrol-1-yl)phenyl];-   Benzenesulfonamide, 4-fluoro-N-[2-(1H-pyrrol-1-yl)phenyl]; and-   2-Thiophenesulfonamide,    5-(3-isoxazolyl)-N-[5-methyl-2-(1H-pyrrol-1-yl)phenyl],

are known, but not as CCR9 or CCR2 antagonists.

Preferred Embodiments I-IV

In one embodiment, Ar is a C₆₋₁₀ aryl.

In one embodiment, Ar is phenyl.

In one embodiment, Ar is a C₅₋₁₀ heteroaryl.

In one embodiment, Ar is a C₅ heteroaryl, preferably with one heteroatomwhich is N, O or S.

In one embodiment, Ar is a C₆₋₁₀ aryl with at least 1 substituents otherthan hydrogen; preferably halogen or alkyl.

In one embodiment, Ar is a C₆₋₁₀ aryl with at least 2 substituents otherthan hydrogen; preferably where at least one is halogen or alkyl.

In one embodiment, Ar is a substituted or unsubstituted bicyclic aryl orsubstituted or unsubstituted bicyclic heteroaryl.

In one embodiment, A is CR⁴.

In one embodiment, A is N.

In one embodiment, R⁸ is C₁₋₈ alkyl or halogen.

In one embodiment, R⁸ is substituted C₁₋₈ alkyl.

In one embodiment, R⁸ is substituted C₁₋₈ alkyl, wherein R⁸ issubstituted with —OH.

In one embodiment, R⁸ is —C(CH₃)₂OH.

In one embodiment, R⁹ is C₁₋₈ alkyl or halogen.

In one embodiment, R⁹ is fluorine.

In one embodiment, X¹ is N, X² is CR⁶ and X³ is CR⁷.

In one embodiment, X¹ is C, X² is N and X³ is CR⁷.

In one embodiment, X¹ is C, X² is CR⁶ and X³ is N.

In one embodiment, X¹ is N, X² is N and X³ is CR⁷.

In one embodiment, X¹ is N, X² is CR⁶ and X³ is N.

In one embodiment, X¹ is C, X² is N and X³ is N.

In one embodiment, X¹ is N, X² is N and X³ is N.

In one embodiment, R² and R³, together with the atoms which theysubstitute form a 5- or 6-membered ring.

In one embodiment, R² and R³, together with the atoms which theysubstitute form phenyl.

In one embodiment, R² and R³, together with the atoms which theysubstitute form a pyridine.

In one embodiment, R² and R³, together with the atoms which theysubstitute form a pyrimidine.

In one embodiment, R² and R³, together with the atoms which theysubstitute form a pyrazine.

In one embodiment, the R⁴ para to the sulfonamide bond is halogen.

In one embodiment, the R⁴ meta to the sulfonamide bond and para to the5-membered ring is halogen.

Preferred Embodiments V-VIII

In one embodiment, the R⁴ para to the sulfonamide bond is halogen.

In one embodiment, the R⁴ meta to the sulfonamide bond and para to the5-membered ring is halogen.

In one embodiment, R⁸ is substituted C₁₋₈ alkyl.

In one embodiment, R⁸ is substituted C₁₋₈ alkyl, wherein R⁸ issubstituted with —OH.

In one embodiment, R⁸ is —C(CH₃)₂OH.

In one embodiment, R⁹ is fluorine.

Preferred Substituents for Formula CI-CVII

In one embodiment, R¹ is unsubstituted or substituted C₁₋₈ alkyl.

In one embodiment, R¹ is substituted C₁₋₈ alkyl, wherein R⁸ issubstituted with —OH.

In one embodiment, R¹ is —C(CH₃)₃

In one embodiment, R¹ is substituted C₁₋₈ alkyl.

In one embodiment, R¹ is —C(CH₃)₂OH.

In one embodiment, each R² is hydrogen.

In one embodiment, at least one R² is fluorine.

In one embodiment, R³ is hydrogen.

In one embodiment, R⁴ is hydrogen.

In one embodiment, R⁵ is halogen, more preferably chlorine.

In one embodiment, R⁶ is hydrogen, halogen, substituted or unsubstitutedC₁₋₈ alkyl, —CO₂R′, —C(O)R′, —C(O)NR′R″, oxo (═O or —O⁻), and —OR′,where R′ and R″ are defined above in the definitions section undersuitable substituents for substituted alkyl. When R⁶ is substitutedalkyl, preferred substituents include halogen, and —OR.

In one embodiment, R⁷ is hydrogen, halogen, substituted or unsubstitutedC₁₋₈ alkyl.

In one embodiment, R⁶ and R⁷ together form a substituted orunsubstituted C₆ aryl.

In one embodiment, R⁶ and R⁷ together form a substituted orunsubstituted C₆ heteroaryl.

In one embodiment, R⁶ and R⁷ together form a substituted orunsubstituted pyridine.

In one embodiment, R⁹ is hydrogen or substituted or unsubstituted C₁₋₈alkyl.

Preferred Embodiments of Formula CCI-CCVI

In one embodiment, R¹ is C₁₋₈ alkyl.

In one embodiment, R¹ is unsubstituted or substituted C₁₋₈ alkyl.

In one embodiment, R¹ is substituted C₁₋₈ alkyl, wherein R⁸ issubstituted with —OH.

In one embodiment, R¹ is C(CH₃)₃

In one embodiment, R¹ is substituted C₁₋₈ alkyl.

In one embodiment, R¹ is —C(CH₃)₂OH.

In one embodiment, each R² is hydrogen.

In one embodiment, R³ is hydrogen.

In one embodiment, R⁴ is halogen, preferably chlorine.

In one embodiment, R⁵ is hydrogen.

In one embodiment, R⁶ and R⁷ together form a substituted orunsubstituted C₆ aryl.

In one embodiment, R⁶ and R⁷ together form a substituted orunsubstituted C₆ heteroaryl.

In one embodiment, R⁶ and R⁷ together form a substituted orunsubstituted pyridine.

Compositions that Modulate Chemokine Activity

In another aspect, the present invention provides compositions thatmodulate chemokine activity, specifically CCR9 activity. Generally, thecompositions for modulating chemokine receptor activity in humans andanimals will comprise a pharmaceutically acceptable excipient or diluentand a compound having any of the formulae (I-VIII).

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. By“pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

The pharmaceutical compositions for the administration of the compoundsof this invention may conveniently be presented in unit dosage form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition the active object compound is included inan amount sufficient to produce the desired effect upon the process orcondition of diseases.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions and self emulsifications as described in U.S. Pat. No.6,451,339, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions. Suchcompositions may contain one or more agents selected from sweeteningagents, flavoring agents, coloring agents and preserving agents in orderto provide pharmaceutically elegant and palatable preparations. Tabletscontain the active ingredient in admixture with other non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be, for example, inertdiluents such as cellulose, silicon dioxide, aluminum oxide, calciumcarbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose,calcium phosphate or sodium phosphate; granulating and disintegratingagents, for example, corn starch, or alginic acid; binding agents, forexample PVP, cellulose, PEG, starch, gelatin or acacia, and lubricatingagents, for example magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated enterically or otherwiseby known techniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. They may also becoated by the techniques described in the U.S. Pat. Nos. 4,256,108;4,166,452; and 4,265,874 to form osmotic therapeutic tablets for controlrelease.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.Additionally, emulsions can be prepared with a non-water miscibleingredient such as oils and stabilized with surfactants such asmono-diglycerides, PEG esters and the like.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil in water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative. and flavoring and coloringagents. Oral solutions can be prepared in combination with, for example,cyclodextrin, PEG and surfactants.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, axed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of the present invention may also be administered in theform of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols. Additionally, the compounds can be administered via oculardelivery by means of solutions or ointments. Still further, transdermaldelivery of the subject compounds can be accomplished by means ofiontophoretic patches and the like.

For topical use, creams, ointments, jellies, solutions or suspensionscontaining the compounds of the present invention are employed. As usedherein, topical application is also meant to include the use of mouthwashes and gargles.

The pharmaceutical compositions and methods of the present invention mayfurther comprise other therapeutically active compounds as noted herein,such as those applied in the treatment of the above mentionedpathological conditions.

In one embodiment, the present invention provides a compositionconsisting of a pharmaceutically acceptable carrier and a compound ofthe invention.

Methods of Treatment

Depending on the disease to be treated and the subject's condition, thecompounds and compositions of the present invention may be administeredby oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous,ICV, intracisternal injection or infusion, subcutaneous injection, orimplant), inhalation, nasal, vaginal, rectal, sublingual, or topicalroutes of administration and may be formulated, alone or together, insuitable dosage unit formulations containing conventional non toxicpharmaceutically acceptable carriers, adjuvants and vehicles appropriatefor each rouse of administration. The present invention alsocontemplates administration of the compounds and compositions of thepresent invention in a depot formulation.

In the treatment or prevention of conditions which require chemokinereceptor modulation an appropriate dosage level will generally be about0.001 to 100 mg per kg patient body weight per day which can beadministered in single or multiple doses. Preferably, the dosage levelwill be about 0.01 to about 25 mg/kg per day; more preferably about 0.05to about 10 mg/kg per day. A suitable dosage level may be about 0.01 to25 mg/kg per day, about 0.05 to 10 mg/kg per day, or about 0.1 to 5mg/kg per day. Within this range the dosage may be 0.005 to 0.05, 0.05to 0.5, 0.5 to 5.0, or 5.0 to 50 mg/kg per day. For oral administration,the compositions are preferably provided in the form of tabletscontaining 1.0 to 1000 milligrams of the active ingredient, particularly1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0,250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0milligrams of the active ingredient for the symptomatic adjustment ofthe dosage to the patient to be treated. The compounds may beadministered on a regimen of 1 to 4 times per day, preferably once ortwice per day.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, hereditary characteristics, generalhealth, sex, diet, mode and time of administration, rate of excretion,drug combination, the severity of the particular condition, and the hostundergoing therapy.

In still other embodiments, the present methods are directed to thetreatment of allergic diseases, wherein a compound or composition of theinvention is administered either alone or in combination with a secondtherapeutic agent, wherein said second therapeutic agent is anantihistamine. When used in combination, the practitioner can administera combination of the compound or composition of the present inventionand a second therapeutic agent. Also, the compound or composition andthe second therapeutic agent can be administered sequentially, in anyorder.

The compounds and compositions of the present invention can be combinedwith other compounds and compositions having related utilities toprevent and treat the condition or disease of interest, such asinflammatory conditions and diseases, including inflammatory boweldisease, allergic diseases, psoriasis, atopic dermatitis and asthma, andthose pathologies noted above. Selection of the appropriate agents foruse in combination therapies can be made one of ordinary skill in theart. The combination of therapeutic agents may act synergistically toeffect the treatment or prevention of the various disorders. Using thisapproach, one may be able to achieve therapeutic efficacy with lowerdosages of each agent, thus reducing the potential for adverse sideeffects.

In treating, preventing, ameliorating, controlling or reducing the riskof inflammation, the compounds of the present invention may be used inconjunction with an antiinflammatory or analgesic agent such as anopiate agonist, a lipoxygenase inhibitor, such as an inhibitor of5-lipoxygenase, a cyclooxygenase inhibitor, such as a cyclooxygenase-2inhibitor, an interleukin inhibitor, such as an interleukin-1 inhibitor,an NMDA antagonist, an inhibitor of nitric oxide or an inhibitor of thesynthesis of nitric oxide, a non-steroidal antiinflammatory agent, or acytokine-suppressing antiinflammatory agent, for example with a compoundsuch as acetaminophen, aspirin, codeine, biological TNF sequestrants,fentanyl, ibuprofen, indomethacin, ketorolac, morphine, naproxen,phenacetin, piroxicam, a steroidal analgesic, sufentanyl, sunlindac,tenidap, and the like.

Similarly, the compounds of the present invention may be administeredwith a pain reliever; a potentiator such as caffeine, an H2-antagonist,simethicone, aluminum or magnesium hydroxide; a decongestant such aspseudophedrine; an antitussive such as codeine; a diuretic; a sedatingor non-sedating antihistamine; a very late antigen (VLA-4) antagonist;an immunosuppressant such as cyclosporin, tacrolimus, rapamycin, EDGreceptor agonists, or other FK-506 type immunosuppressants; a steroid; anon-steroidal anti-asthmatic agent such as a β2-agonist, leukotrieneantagonist, or leukotriene biosynthesis inhibitor; an inhibitor ofphosphodiesterase type IV (PDE-IV); a cholesterol lowering agent such asa HMG-CoA reductase inhibitor, sequestrant, or cholesterol absorptioninhibitor; and an anti-diabetic agent such as insulin, α-glucosidaseinhibitors or glitazones.

The weight ratio of the compound of the present invention to the secondactive ingredient may be varied and will depend upon the effective doseof each ingredient. Generally, an effective dose of each will be used.Thus, for example, when a compound of the present invention is combinedwith an NSAID the weight ratio of the compound of the present inventionto the NSAID will generally range from about 1000:1 to about 1:1000,preferably about 200:1 to about 1:200. Combinations of a compound of thepresent invention and other active ingredients will generally also bewithin the aforementioned range, but in each case, an effective dose ofeach active ingredient should be used.

Methods of Treating or Preventing CCR9-mediated Conditions or Diseases

In yet another aspect, the present invention provides methods oftreating or preventing a CCR9-mediated condition or disease byadministering to a subject having such a condition or disease atherapeutically effective amount of any compound of formulae above.Compounds for use in the present methods include those compoundsaccording to the above formulae, those provided above as embodiments,those specifically exemplified in the Examples below, and those providedwith specific structures herein. The “subject” is defined herein toinclude animals such as mammals, including, but not limited to, primates(e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats,mice and the like. In preferred embodiments, the subject is a human.

As used herein, the phrase “CCR9-mediated condition or disease” andrelated phrases and terms refer to a condition or disease characterizedby inappropriate, i.e., less than or greater than normal, CCR9functional activity. Inappropriate CCR9 functional activity might ariseas the result of CCR9 expression in cells which normally do not expressCCR9, increased CCR9 expression (leading to, e.g., inflammatory andimmunoregulatory disorders and diseases) or decreased CCR9 expression.Inappropriate CCR9 functional activity might also arise as the result ofTECK secretion by cells which normally do not secrete TECK, increasedTECK expression (leading to, e.g., inflammatory and immunoregulatorydisorders and diseases) or decreased TECK expression. A CCR9-mediatedcondition or disease may be completely or partially mediated byinappropriate CCR9 functional activity. However, a CCR9-mediatedcondition or disease is one in which modulation of CCR9 results in someeffect on the underlying condition or disease (e.g., a CCR9 antagonistresults in some improvement in patient well being in at least somepatients).

The term “therapeutically effective amount” means the amount of thesubject compound that will elicit the biological or medical response ofa cell, tissue, system, or animal, such as a human, that is being soughtby the researcher, veterinarian, medical doctor or other treatmentprovider.

Diseases and conditions associated with inflammation, immune disorders,infection and cancer can be treated or prevented with the presentcompounds, compositions, and methods. In one group of embodiments,diseases or conditions, including chronic diseases, of humans or otherspecies can be treated with inhibitors of CCR9 function. These diseasesor conditions include: (1) allergic diseases such as systemicanaphylaxis or hypersensitivity responses, drug allergies, insect stingallergies and food allergies, (2) inflammatory bowel diseases, such asCrohn's disease, ulcerative colitis, microscopic colitis, ileitis andenteritis, (3) vaginitis, (4) psoriasis and inflammatory dermatoses suchas dermatitis, eczema, atopic dermatitis, allergic contact dermatitis,urticaria and pruritus, (5) vasculitis, (6) spondyloarthropathies, (7)scleroderma, (8) asthma and respiratory allergic diseases such asallergic asthma, allergic rhinitis, hypersensitivity lung diseases andthe like, (9) autoimmune diseases, such as fibromyalagia, scleroderma,ankylosing spondylitis, juvenile RA, Still's disease, polyarticularjuvenile RA, pauciarticular juvenile RA, polymyalgia rheumatica,rheumatoid arthritis, psoriatic arthritis, osteoarthritis, polyarticulararthritis, multiple sclerosis, systemic lupus erythematosus, type Idiabetes, type II diabetes, glomerulonephritis, and the like, (10) graftrejection (including allograft rejection), (11) graft-v-host disease(including both acute and chronic), (12) other diseases in whichundesired inflammatory responses are to be inhibited, such asatherosclerosis, myositis, neurodegenerative diseases (e.g., Alzheimer'sdisease), encephalitis, meningitis, hepatitis, nephritis, sepsis,sarcoidosis, allergic conjunctivitis, otitis, chronic obstructivepulmonary disease, sinusitis, Behcet's syndrome and gout, (13) immunemediated food allergies such as Coeliac (Celiac) disease (14) pulmonaryfibrosis and other fibrotic diseases, (15) irritable bowel syndrome,(16) primary sclerosing cholangitis and (17) cancer (including bothprimary and metastatic).

In another group of embodiments, diseases or conditions can be treatedwith modulators and agonists of CCR9 function. Examples of diseases tobe treated by modulating CCR9 function include cancers, cardiovasculardiseases, diseases in which angiogenesis or neovascularization play arole (neoplastic diseases, retinopathy and macular degeneration),infectious diseases (viral infections, e.g., HIV infection, andbacterial infections) and immunosuppressive diseases such as organtransplant conditions and skin transplant conditions. The term “organtransplant conditions” is means to include bone marrow transplantconditions and solid organ (e.g., kidney, liver, lung, heart, pancreasor combination thereof) transplant conditions.

Preferably, the present methods are directed to the treatment ofdiseases or conditions selected from inflammatory bowel diseaseincluding Crohn's disease and Ulcerative Colitis, allergic diseases,psoriasis, atopic dermatitis and asthma, autoimmune disease such asrheumatoid arthritis and immune-mediated food allergies such as Coelaicdisease.

In yet other embodiments, the present methods are directed to thetreatment of psoriasis where a compound or composition of the inventionis used alone or in combination with a second therapeutic agent such asa corticosteroid, a lubricant, a keratolytic agent, a vitamin D₃derivative, PUVA and anthralin.

In other embodiments, the present methods are directed to the treatmentof atopic dermatitis using a compound or composition of the inventioneither alone or in combination with a second therapeutic agent such as alubricant and a corticosteroid.

In further embodiments, the present methods are directed to thetreatment of asthma using a compound or composition of the inventioneither alone or in combination with a second therapeutic agent such as aβ2-agonist and a corticosteroid.

Preparation of Modulators

The following examples are offered to illustrate, but not to limit, theclaimed invention.

Additionally, those skilled in the art will recognize that the moleculesclaimed in this patent may be synthesized using a variety of standardorganic chemistry transformations.

Certain general reaction types employed widely to synthesize targetcompounds in this invention are summarized in the examples.Specifically, generic procedures for sulfonamide formation, pyridineN-oxide formation and 2-aminophenyl-arylmethanone synthesis viaFriedel-Crafts type approaches are given, but numerous other standardchemistries are described within and were employed routinely.

While not intended to be exhaustive, representative synthetic organictransformations which can be used to prepare compounds of the inventionare included below.

These representative transformations include; standard functional groupmanipulations; reductions such as nitro to amino; oxidations offunctional groups including alcohols and pyridines; aryl substitutionsvia IPSO or other mechanisms for the introduction of a variety of groupsincluding nitrile, methyl and halogen; protecting group introductionsand removals; Grignard formation and reaction with an electrophile;metal-mediated cross couplings including but not limited to Buckwald,Suzuki and Sonigashira reactions; halogenations and other electrophilicaromatic substitution reactions; diazonium salt formations and reactionsof these species; etherifications; cyclative condensations,dehydrations, oxidations and reductions leading to heteroaryl groups;aryl metallations and transmetallations and reaction of the ensuingaryl-metal species with an electrophile such as an acid chloride orWeinreb amide; amidations; esterifications; nucleophilic substitutionreactions; alkylations; acylations; sulfonamide formation;chlorosulfonylations; ester and related hydrolyses, and the like.

Certain molecules claimed in this patent can exist in differentenantiomeric and diastereomeric forms and all such variants of thesecompounds are within the scope of the invention.

In the descriptions of the syntheses that follow, some precursors wereobtained from commercial sources. These commercial sources includeAldrich Chemical Co., Acros Organics, Ryan Scientific Incorporated,Oakwood Products Incorporated, Lancaster Chemicals, Sigma Chemical Co.,Lancaster Chemical Co., TCI-America, Alfa Aesar, Davos Chemicals, andGFS Chemicals.

Compounds of the invention, including those listed in the table ofactivities, can be made by the methods and approaches described in thefollowing experimental section, and by the use of standard organicchemistry transformations that are well known to those skilled in theart.

EXAMPLES

Exemplary compounds used in the method of the invention and inpharmaceutical compositions of the invention include but are not limitedto the compounds listed in the following table. Pharmaceuticallyacceptable salts of the compounds listed in this table are also usefulin the method of the invention and in pharmaceutical compositions of theinvention. These compounds are within the scope of this invention andwere tested for CCR9 activity as described below.

Reagents and solvents used below can be obtained from commercial sourcessuch as Aldrich Chemical Co. (Milwaukee, Wis., USA). ¹H-NMR wererecorded on a Varian Mercury 400 MHz NMR spectrometer. Significant peaksare tabulated in the order: multiplicity (br, broad; s, singlet; d,doublet; t, triplet; q, quartet; m, multiplet) and number of protons.Mass spectrometry results are reported as the ratio of mass over charge,followed by the relative abundance of each ion (in parenthesis). Intables, a single m/e value is reported for the M+H (or, as noted, M−H)ion containing the most common atomic isotopes. Isotope patternscorrespond to the expected formula in all cases. Electrospray ionization(ESI) mass spectrometry analysis was conducted on a Hewlett-Packard MSDelectrospray mass spectrometer using the HP1100 HPLC for sampledelivery. Normally the analyte was dissolved in methanol at 0.1 mg/mLand 1 microliter was infused with the delivery solvent into the massspectrometer, which scanned from 100 to 1500 daltons. All compoundscould be analyzed in the positive ESI mode, using acetonitrile/waterwith 1% formic acid as the delivery solvent. The compounds providedbelow could also be analyzed in the negative ESI mode, using 2 mM NH₄OAcin acetonitrile/water as delivery system.

Examples

Exemplary compounds used in the method of the invention and inpharmaceutical compositions of the invention include but are not limitedto the compounds listed in Table 1. Pharmaceutically acceptable salts ofthe compounds listed in Table 1 are also useful in the method of theinvention and in pharmaceutical compositions of the invention.

The compounds shown in Table 1 can be synthesized using the method shownin the chart and detailed below.

Compounds of the invention were assayed for activity in the chemotaxisassay described herein under the section below titled “Example of invitro assay” where the “chemotaxis assay” is described. All compoundslisted in Table 1 has IC₅₀ of <1000 nM in the chemotaxis assay.

TABLE 1 Exemplary compounds with CCR9 activity in one of the chemotaxis,binding or calcium mobilization assays, with IC50 < 1000 nM ObservedSynthetic Molecular STRUCTURE Method Ion (M + 1) 1.

T 441.0 2.

T 455.0 3.

D 435.0 4.

D 460.0 5.

D 460.0 6.

D 390.0 7.

D 424.0 8.

D 433.1 9.

D 462.1 10.

D 432.1 11.

D 404.0 12.

D 432.1 13.

D 439.0 14.

D 440.0 15.

D 440.0 16.

D 441.0 17.

D 442.0 18.

D 442.0 19.

D 418.0 20.

D 418.0 21.

D 432.1 22.

D 441.0 23.

D 441.0 24.

D 457.0 25.

D 442.0 26.

D 442.0 27.

D 454.0 28.

D 455.0 29.

D 441.0 30.

D 441.0 31.

D 457.0 32.

D 440.0 33.

D 440.0 34.

D 440.0 35.

E 435.0 36.

E 461.1 37.

G 444.0 38.

G 484.0 39.

G 456.1 40.

G 457.0 41.

G 457.1 42.

G 391.0 43.

G 463.0 44.

G 455.0 45.

G 456.4 46.

G 352.0 47.

G 457.0 48.

H 448.0 49.

H 462.0 50.

H 474.0 51.

H 517.1 52.

H 434.0 53.

I 435.0 54.

J 484.0 55.

J 457.0 56.

J 456.0 57.

J 457.0 58.

J 527.5 59.

J 578.6 60.

L 424.1 61.

L 433.1 62.

M 460.4 63.

M 446.1 64.

N 504.4 65.

N 460.1 66.

N 474.1 67.

N 488.1 68.

O 488.4 69.

O 524.0 70.

Q 433.1 71.

Q 419.3 72.

Q 490.4 73.

Q 448.4 74.

Q 474.4 75.

R 489.0 76.

S 448.1 77.

D 442.0 78.

D 456.0 79.

D 442.1 80.

D 442.1 81.

D 456.0 82.

D 443.0 83.

D 463.0 84.

D 423.1 85.

D 425.0 86.

D 405.0 87.

D 467.0 88.

D 405.0 89.

D 433.1 90.

D 467.0 91.

D 419.0 92.

D 440.0 93.

D 441.0 94.

D 441.0 95.

D 442.0 96.

D 443.0 97.

D 419.0 98.

D 433.1 99.

E 502.1 100.

E 504.0 101.

E 488.0 102.

E 517.1 103.

E 474.0 104.

E 490.1 105.

E 545.1 106.

E 531.0 107.

E 519.1 108.

E 500.0 109.

E 448.0 110.

E 462.0 111.

E 462.0 112.

E 476.0 113.

F 435.0 114.

G 406.0 115.

H 448.0 116.

I 458.0 117.

V 441.1 118.

V 440.0 119.

G 428.0 120.

W 443.0 121.

W 457.0 122.

X 428.0 123.

X 443.1 124.

X 457.1 125.

X 499.1 126.

Y 466.0 (M + Na) 127.

W 471.1 128.

W 483.1 129.

W 499.1 130.

W 501.1 131.

Z 458.0 132.

G 486.4 133.

G 428.0 134.

G 411.0 135.

AA 430.1 136.

BB 498.0 137.

Y 440.0 138.

CC 405.4 139.

DD 449.1 140.

G 512.0 141.

EE 429.3 142.

FF 433.4 143.

GG 463.4 144.

HH 448.4 145.

HH 476.5 146.

HH 474.4 147.

HH 462.4 148.

HH 504.5 149.

II 488.1 150.

JJ 449.3 151.

KK 472.0 152.

LL 420.1 153.

MM 461.4 154.

MM 433.4 155.

MM 489.4 156.

MM 447.4 157.

NN 476.5 158.

S 462.4 159.

PP 484.0 (M + Na) 160.

PP 480.1 161.

PP 500.0 (M + Na) 162.

PP 496.0 (M + Na) 163.

PP 512.0

The names for the structures 1-163 are provided in the following table:

Structure Name 14-tert-butyl-N-(4-chloro-2-(1H-pyrazolo[3,4-b]pyridin-3-yl)phenyl)benzenesulfonamide 24-tert-butyl-N-(4-chloro-2-(1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)phenyl)benzenesulfonamide 34-tert-butyl-N-(4-chloro-2-(4-(methoxymethyl)-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide 4N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chloro-5-fluorophenyl)-4-tert-butylbenzenesulfonamide 51-(2-(4-tert-butylphenylsulfonamido)-4-chlorophenyl)-N,N-dimethyl-1H-pyrazole-4-carboxamide 64-tert-butyl-N-(4-chloro-2-(1H-pyrazol-1-yl)phenyl)benzenesulfonamide 74-tert-butyl-N-(4-chloro-2-(4-chloro-1H-pyrazol-1-yl)phenyl)benzenesulfonamide 84-tert-butyl-N-(4-chloro-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide 9 ethyl1-(2-(4-tert-butylphenylsulfonamido)-5-chlorophenyl)-1H-pyrazole-4-carboxylate 10 4-tert-butyl-N-(4-chloro-2-(4-isopropyl-1H-pyrazol-1-yl)phenyl)benzenesulfonamide 114-tert-butyl-N-(4-chloro-2-(2-methyl-1H-imidazol-1-yl)phenyl)benzenesulfonamide 124-tert-butyl-N-(4-chloro-2-(2-isopropyl-1H-imidazol-1-yl)phenyl)benzenesulfonamide 134-tert-butyl-N-(4-chloro-2-(1H-indol-1-yl)phenyl)benzenesulfonamide 144-tert-butyl-N-(4-chloro-2-(1H-imidazo[4,5-b]pyridin-1-yl)phenyl)benzenesulfonamide 154-tert-butyl-N-(4-chloro-2-(1H-indazol-1-yl)phenyl)benzenesulfonamide 16N-(2-(1H-benzo[d][1,2,3]triazol-1-yl)-4-chlorophenyl)-4-tert-butylbenzenesulfonamide 174-tert-butyl-N-(4-chloro-2-(9H-purin-9-yl)phenyl)benzenesulfonamide 184-tert-butyl-N-(4-chloro-2-(7H-purin-7-yl)phenyl)benzenesulfonamide 194-tert-butyl-N-(4-chloro-2-(2-ethyl-1H-imidazol-1-yl)phenyl)benzenesulfonamide 204-tert-butyl-N-(4-chloro-2-(2,4-dimethyl-1H-imidazol-1-yl)phenyl)benzenesulfonamide 214-tert-butyl-N-(4-chloro-2-(2-ethyl-4-methyl-1H-imidazol-1-yl)phenyl)benzenesulfonamide 224-tert-butyl-N-(4-chloro-2-(1H-imidazo[4,5-b]pyridin-1-yl)phenyl)benzenesulfonamide 234-tert-butyl-N-(4-chloro-2-(3H-imidazo[4,5-b]pyridin-3-yl)phenyl)benzenesulfonamide 24N-(2-(2-amino-7H-purin-7-yl)-4-chlorophenyl)-4-tert-butylbenzenesulfonamide25 N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-tert-butylbenzenesulfonamide 26N-(2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-4-chlorophenyl)-4-tert-butylbenzenesulfonamide 274-tert-butyl-N-(4-chloro-2-(2-methyl-1H-benzo[d]imidazol-1-yl)phenyl)benzenesulfonamide 284-tert-butyl-N-(4-chloro-2-(2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)phenyl)benzenesulfonamide 294-tert-butyl-N-(4-chloro-2-(1H-imidazo[4,5-c]pyridin-1-yl)phenyl)benzenesulfonamide 304-tert-butyl-N-(4-chloro-2-(3H-imidazo[4,5-c]pyridin-3-yl)phenyl)benzenesulfonamide 314-tert-butyl-N-(4-chloro-2-(2-oxo-1H-imidazo[4,5-c]pyridin-3(2H)-yl)phenyl)benzenesulfonamide 324-tert-butyl-N-(4-chloro-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)phenyl)benzenesulfonamide 334-tert-butyl-N-(4-chloro-2-(1H-pyrrolo[3,2-c]pyridin-1-yl)phenyl)benzenesulfonamide 344-tert-butyl-N-(4-chloro-2-(1H-pyrrolo[3,2-b]pyridin-1-yl)phenyl)benzenesulfonamide 351-(2-(4-tert-butylphenylsulfonamido)-5-chlorophenyl)-N,N-dimethyl-1H-pyrazole-4-carboxamide 361-(2-(4-tert-butylphenylsulfonamido)-5-chlorophenyl)-1H-pyrazole-4-carboxamide 37N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-isopropoxybenzenesulfonamide 38N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-(4-methyltetrahydro-2H-pyran-4-yl)benzenesulfonamide 39N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-tert-pentylbenzenesulfonamide 40N-(2-(2-amino-9H-purin-9-yl)-4-chlorophenyl)-4-tert-butylbenzenesulfonamide41N-(2-(6-amino-9H-purin-9-yl)-4-chlorophenyl)-4-tert-butylbenzenesulfonamide424-tert-butyl-N-(4-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide43 ethyl1-(2-(4-tert-butylphenylsulfonamido)-5-chlorophenyl)-1H-1,2,3-triazole-4-carboxylate 44N-(2-(5-amino-1H-pyrrolo[3,2-b]pyridin-1-yl)-4-chlorophenyl)-4-tert-butylbenzenesulfonamide 454-tert-butyl-N-(4-chloro-2-(5-methyl-1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)phenyl)benzenesulfonamide 46N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-isopropylbenzenesulfonamide 47N-(2-(5-amino-1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-tert-butylbenzenesulfonamide 481-(2-(4-tert-butylphenylsulfonamido)-5-chlorophenyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide 491-(2-(4-tert-butylphenylsulfonamido)-5-chlorophenyl)-N,N-dimethyl-1H-1,2,3-triazole-4-carboxamide 50N-(2-(4-(azetidine-1-carbonyl)-1H-1,2,3-triazol-1-yl)-4-chlorophenyl)-4-tert-butylbenzenesulfonamide 514-tert-butyl-N-(4-chloro-2-(4-(4-methylpiperazine-1-carbonyl)-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide 521-(2-(4-tert-butylphenylsulfonamido)-5-chlorophenyl)-1H-1,2,3-triazole-4-carboxamide 531-(2-(4-tert-butylphenylsulfonamido)-5-chlorophenyl)-1H-1,2,3-triazole-4-carboxylic acid 544-tert-butyl-N-(4-chloro-2-(4-(dimethylamino)-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)benzenesulfonamide 55N-(2-(4-amino-1H-[1,2,3]triazolo[4,5-c]pyridin-1-yl)-4-chlorophenyl)-4-tert-butylbenzenesulfonamide 56N-(2-(4-amino-1H-pyrazolo[4,3-c]pyridin-1-yl)-4-chlorophenyl)-4-tert-butylbenzenesulfonamide 574-tert-butyl-N-(4-chloro-2-(4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-1-yl)phenyl)benzenesulfonamide 584-tert-butyl-N-(4-chloro-2-(4-morpholino-1H-[1,2,3]triazolo[4,5-c]pyridin-1-yl)phenyl)benzenesulfonamide 594-tert-butyl-N-(4-morpholino-2-(4-morpholino-1H-[1,2,3]triazolo[4,5-c]pyridin-1-yl)phenyl)benzenesulfonamide 604-tert-butyl-N-(3,4-dichloro-2-(1H-pyrazol-1-yl)phenyl)benzenesulfonamide61 N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-cyanophenyl)-4-tert-butylbenzenesulfonamide 624-tert-butyl-N-(4-chloro-2-(5-methyl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)phenyl)benzenesulfonamide 634-tert-butyl-N-(4-chloro-2-(4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)phenyl)benzenesulfonamide 644-tert-butyl-N-(4-chloro-2-(4-(2-methoxyethyl)-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)phenyl)benzenesulfonamide 654-tert-butyl-N-(4-chloro-2-(4-methyl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)phenyl)benzenesulfonamide 664-tert-butyl-N-(4-chloro-2-(4-ethyl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)phenyl)benzenesulfonamide 674-tert-butyl-N-(4-chloro-2-(4-isopropyl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)phenyl)benzenesulfonamide 68N-(2-(4-acetyl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-tert-butylbenzenesulfonamide 694-tert-butyl-N-(4-chloro-2-(4-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)phenyl)benzenesulfonamide 704-tert-butyl-N-(4-chloro-2-(5-isopropyl-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide 714-tert-butyl-N-(4-chloro-2-(5-ethyl-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide 724-tert-butyl-N-(4-chloro-2-(5-(morpholinomethyl)-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide 734-tert-butyl-N-(4-chloro-2-(4-((dimethylamino)methyl)-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide 744-tert-butyl-N-(4-chloro-2-(5-(pyrrolidin-1-ylmethyl)-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide 75N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-3-fluoro-4-morpholinobenzenesulfonamide 764-tert-butyl-N-(4-chloro-2-(4-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)phenyl)benzenesulfonamide 774-tert-butyl-N-(5-chloro-2-(1H-pyrazolo[4,3-b]pyridin-1-yl)pyridin-3-yl)benzenesulfonamide 784-tert-butyl-N-(5-chloro-2-(5-methyl-1H-pyrazolo[4,3-b]pyridin-1-yl)pyridin-3-yl)benzenesulfonamide 794-tert-butyl-N-(5-chloro-2-(1H-imidazo[4,5-b]pyridin-1-yl)pyridin-3-yl)benzenesulfonamide 804-tert-butyl-N-(5-chloro-2-(3H-imidazo[4,5-b]pyridin-3-yl)pyridin-3-yl)benzenesulfonamide 81N-(2-(5-amino-1H-pyrrolo[3,2-b]pyridin-1-yl)-5-chloropyridin-3-yl)-4-tert-butylbenzenesulfonamide 82N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-5-chloropyridin-3-yl)-4-tert-butylbenzenesulfonamide 83 ethyl1-(3-(4-tert-butylphenylsulfonamido)-5-chloropyridin-2-yl)-1H-pyrazole-4-carboxylate 84N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-5-methylpyridin-3-yl)-4-tert-butylbenzenesulfonamide 854-tert-butyl-N-(5-chloro-2-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)benzenesulfonamide 864-tert-butyl-N-(5-chloro-2-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl)benzenesulfonamide 874-tert-butyl-N-(5-chloro-2-(4-phenyl-1H-imidazol-1-yl)pyridin-3-yl)benzenesulfonamide 884-tert-butyl-N-(5-chloro-2-(2-methyl-1H-imidazol-1-yl)pyridin-3-yl)benzenesulfonamide 894-tert-butyl-N-(5-chloro-2-(2-isopropyl-1H-imidazol-1-yl)pyridin-3-yl)benzenesulfonamide 904-tert-butyl-N-(5-chloro-2-(2-phenyl-1H-imidazol-1-yl)pyridin-3-yl)benzenesulfonamide 914-tert-butyl-N-(5-chloro-2-(2-ethyl-1H-imidazol-1-yl)pyridin-3-yl)benzenesulfonamide 924-tert-butyl-N-(5-chloro-2-(1H-indol-1-yl)pyridin-3-yl)benzenesulfonamide93 N-(2-(1H-benzo[d]imidazol-1-yl)-5-chloropyridin-3-yl)-4-tert-butylbenzenesulfonamide 944-tert-butyl-N-(5-chloro-2-(1H-indazol-1-yl)pyridin-3-yl)benzenesulfonamide95 N-(2-(1H-benzo[d][1,2,3]triazol-1-yl)-5-chloropyridin-3-yl)-4-tert-butylbenzenesulfonamide 964-tert-butyl-N-(5-chloro-2-(9H-purin-9-yl)pyridin-3-yl)benzenesulfonamide97 4-tert-butyl-N-(5-chloro-2-(2,4-dimethyl-1H-imidazol-1-yl)pyridin-3-yl)benzenesulfonamide 984-tert-butyl-N-(5-chloro-2-(2-ethyl-4-methyl-1H-imidazol-1-yl)pyridin-3-yl)benzenesulfonamide 994-tert-butyl-N-(5-chloro-2-(4-(piperidine-1-carbonyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzenesulfonamide 1004-tert-butyl-N-(5-chloro-2-(4-(morpholine-4-carbonyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzenesulfonamide 1014-tert-butyl-N-(5-chloro-2-(4-(pyrrolidine-1-carbonyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzenesulfonamide 1024-tert-butyl-N-(5-chloro-2-(4-(4-methylpiperazine-1-carbonyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzenesulfonamide 103N-(2-(4-(azetidine-1-carbonyl)-1H-pyrazol-1-yl)-5-chloropyridin-3-yl)-4-tert-butylbenzenesulfonamide 1041-(3-(4-tert-butylphenylsulfonamido)-5-chloropyridin-2-yl)-N-isopropyl-N-methyl-1H-pyrazole-4-carboxamide 1054-tert-butyl-N-(5-chloro-2-(4-(4-isopropylpiperazine-1-carbonyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzenesulfonamide 1064-tert-butyl-N-(5-chloro-2-(4-(3-(dimethylamino)pyrrolidine-1-carbonyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzenesulfonamide 1071-(3-(4-tert-butylphenylsulfonamido)-5-chloropyridin-2-yl)-N-(2-(dimethylamino)ethyl)-N-methyl-1H-pyrazole-4-carboxamide 1084-tert-butyl-N-(5-chloro-2-(4-(1,2,3,6-tetrahydropyridine-1-carbonyl)-1H-pyrazol-1-yl)pyridin-3-yl)benzenesulfonamide 1091-(3-(4-tert-butylphenylsulfonamido)-5-chloropyridin-2-yl)-N-methyl-1H-pyrazole-4-carboxamide 1101-(3-(4-tert-butylphenylsulfonamido)-5-chloropyridin-2-yl)-N,N-dimethyl-1H-pyrazole-4-carboxamide 1111-(3-(4-tert-butylphenylsulfonamido)-5-chloropyridin-2-yl)-N,3-dimethyl-1H-pyrazole-4-carboxamide 1121-(3-(4-tert-butylphenylsulfonamido)-5-chloropyridin-2-yl)-N,N,3-trimethyl-1H-pyrazole-4-carboxamide 1131-(3-(4-tert-butylphenylsulfonamido)-5-chloropyridin-2-yl)-1H-pyrazole-4-carboxylic acid 114N-(2-(4-amino-1H-pyrazol-1-yl)-5-chloropyridin-3-yl)-4-tert-butylbenzenesulfonamide 115N-(1-(3-(4-tert-butylphenylsulfonamido)-5-chloropyridin-2-yl)-1H-pyrazol-4-yl)acetamide 1164-tert-butyl-N-(5-chloro-2-(4-(oxazol-2-yl)-1H-pyrazol-1-yl)pyridin-3-yl)benzenesulfonamide 1174-tert-butyl-N-(4-chloro-2-(1H-indazol-3-yl)phenyl)benzenesulfonamide118 4-tert-butyl-N-(4-chloro-2-(1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)benzenesulfonamide 119N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-acetylbenzenesulfonamide 120N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-(1-(hydroxyimino)ethyl)benzenesulfonamide 121N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-(1-(methoxyimino)ethyl)benzenesulfonamide 122N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-(1-aminoethyl)benzenesulfonamide 123N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-(1-(methylamino)ethyl)benzenesulfonamide 124N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-(1-(dimethylamino)ethyl)benzenesulfonamide 125N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-(1-morpholinoethyl)benzenesulfonamide 126 N-(4-Chloro-2[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-4-(1-hydroxy-1-methyl-ethyl)-benzene-sulfonamide 127N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-(1-(ethoxyimino)ethyl)benzenesulfonamide 128N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-(1-(allyloxyimino)ethyl)benzenesulfonamide 129N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-(1-(tert-butoxyimino)ethyl)benzenesulfonamide 1302-(1-(4-(N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)sulfamoyl)phenyl)ethylideneaminooxy)acetic acid 131N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-(1-hydroxy-2-methylpropan-2-yl)benzenesulfonamide 132 methyl2-(4-(N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)sulfamoyl)phenyl)-2-methylpropanoate 133N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-isopropylbenzenesulfonamide 134N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-cyanobenzenesulfonamide 135N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-(1-hydroxyethyl)benzenesulfonamide 136N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzenesulfonamide 137N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-(2-hydroxybutan-2-yl)benzenesulfonamide 1384-tert-butyl-N-(4-chloro-2-(5-methyl-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide 1394-tert-butyl-N-(4-chloro-2-(4-(1-hydroxyethyl)-5-methyl-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide 140N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-iodobenzenesulfonamide 1414-tert-butyl-N-(4-chloro-2-(4-ethynyl-5-methyl-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide 1424-tert-butyl-N-(4-chloro-2-(4-ethyl-5-methyl-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide 143 methyl1-(2-(4-tert-butylphenylsulfonamido)-5-chlorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylate 1444-tert-butyl-N-(4-chloro-2-(5-methyl-4-((methylamino)methyl)-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide 1454-tert-butyl-N-(4-chloro-2-(4-((isopropylamino)methyl)-5-methyl-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide 1464-tert-butyl-N-(4-chloro-2-(4-((cyclopropylamino)methyl)-5-methyl-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide 1474-tert-butyl-N-(4-chloro-2-(4-((dimethylamino)methyl)-5-methyl-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide 1484-tert-butyl-N-(4-chloro-2-(5-methyl-4-(morpholinomethyl)-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide 1494-tert-butyl-N-(4-chloro-2-(5-methyl-4-(thiazol-2-yl)-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide 1501-(2-(4-tert-butylphenylsulfonamido)-5-chlorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid 1514-tert-butyl-N-(4-chloro-2-(5-methyl-4-(oxazol-2-yl)-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide 1524-tert-butyl-N-(4-chloro-2-(4-(hydroxymethyl)-1H-pyrazol-1-yl)phenyl)benzenesulfonamide 1534-tert-butyl-N-(4-chloro-2-(4-((isopropylamino)methyl)-1H-pyrazol-1-yl)phenyl)benzenesulfonamide 1544-tert-butyl-N-(4-chloro-2-(4-((methylamino)methyl)-1H-pyrazol-1-yl)phenyl)benzenesulfonamide 1554-tert-butyl-N-(4-chloro-2-(4-(morpholinomethyl)-1H-pyrazol-1-yl)phenyl)benzenesulfonamide 1564-tert-butyl-N-(4-chloro-2-(4-((dimethylamino)methyl)-1H-pyrazol-1-yl)phenyl)benzenesulfonamide 157 ethyl1-(2-(4-tert-butylphenylsulfonamido)-5-chlorophenyl)-5-methyl-1H-pyrazole-4-carboxylate 1584-tert-butyl-N-(4-chloro-2-(4-(2-hydroxypropan-2-yl)-5-methyl-1H-pyrazol-1-yl)phenyl)benzenesulfonamide 159N-(4-Chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-3-fluoro-4-(1-hydroxy-1-methyl-ethyl)-benzenesulfonamide 160N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-(2-hydroxypropan-2-yl)-3-methylbenzenesulfonamide 161N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-3-chloro-4-(2-hydroxypropan-2-yl)benzenesulfonamide 162N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-(2-hydroxypropan-2-yl)-3-methoxybenzenesulfonamide 163N-(2-(1H-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-4-chlorophenyl)-4-(2-hydroxypropan-2-yl)-3-(trifluoromethyl)benzenesulfonamide

Reagents and solvents used below can be obtained from commercial sourcessuch as Aldrich Chemical Co. (Milwaukee, Wis., USA). ¹H-NMR wererecorded on a Varian Mercury 400 MHz NMR spectrometer. Significant peaksare tabulated in the order: multiplicity (br, broad; s, singlet; d,doublet; t, triplet; q, quartet; m, multiplet) and number of protons.Mass spectrometry results are reported as the ratio of mass over charge,followed by the relative abundance of each ion (in parenthesis). Intables, a single m/e value is reported for the M+H (or, as noted, M−H,M+Na, etc.) ion containing the most common atomic isotopes. Isotopepatterns correspond to the expected formula in all cases. Electrosprayionization (ESI) mass spectrometry analysis was conducted on aHewlett-Packard MSD electrospray mass spectrometer using the HP1100 HPLCfor sample delivery. Normally the analyte was dissolved in methanol at0.1 mg/mL and 1 microliter was infused with the delivery solvent intothe mass spectrometer, which scanned from 100 to 1500 daltons. Allcompounds could be analyzed in the positive ESI mode, usingacetonitrile/water with 1% formic acid as the delivery solvent. Thecompounds provided below could also be analyzed in the negative ESImode, using 2 mM NH₄OAc in acetonitrile/water as delivery system.

General Procedure A

Example 4-tert-Butyl-N-(4-chloro-2-iodo-phenyl)-benzenesulfonamide

A 100 mL round-bottom flask was charged with 2-iodo-4-chloroaniline(8.40 g, 33.2 mmol) and 4-tert-butyl benzenesulfonyl chloride (8.28 g,35.5 mmol). The flask was evacuated and purged with nitrogen, followedby the addition of pyridine (33 mL). The homogeneous purple solution wasstirred 4 hours (during which pyridine salts crashed out), and thenpoured onto a rapidly stirring cold slurry of 6 M HCl (66 mL) (formed byplacing the acidic solution in acetonic dry ice). The resultantprecipitated sulfonamide was filtered, washed thoroughly with 10% HCl,and dried in vacuo to afford 15.586 g of a purplish solid. To the crudesulfonamide was subsequently added 200 mL EtOH and the heterogeneouspurple solution was vigorously stirred and heated until the volume wasreduced to ˜150 mL. The solution was then cooled to ambient temperatureovernight and placed in the freezer for 2 hours, during which thesulfonamide recrystallized from solution. The solid was filtered andwashed with cold MeOH (0° C.) to produce the pure sulfonamide (14.2 g,95%) as a white solid: MS (ES) M+H expected 450.0, found 450.1.

Example4-tert-Butyl-N-(4-chloro-5-fluoro-2-iodo-phenyl)-benzenesulfonamide

Step 1: Iodine (873 mg, 3.44 mmol) was added to a solution of4-chloro-3-fluoroaniline (500 mg, 3.44 mmol) and potassium hydroxide(193 mg, 3.44 mmol) in N,N-dimethylformamide (“DMF”) (10 mL) and thereaction was stirred at 60° C. for 18 hours. The crude mixture wassubsequently partitioned with ethyl acetate (20 mL) and saturatedammonium chloride (20 mL) and the layers separated. The organic layerwas washed with saturated ammonium chloride (3×20 mL), dried overmagnesium sulfate, filtered, and concentrated in vacuo. The crudematerial was purified by flash column chromatography (0-50% ethylacetate in hexanes) to afford the desired iodoaniline (234 mg, 25%).

Step 2:4-tert-Butyl-N-(4-chloro-5-fluoro-2-iodo-phenyl)-benzenesulfonamide wassynthesized from the above iodoaniline and 4-tert-butyl benzenesulfonylchloride according to general procedure A: MS (ES) M+H expected 468.0,found 467.9.

ExampleN-(2-Bromo-5-chloro-pyridin-3-yl)-4-tert-butyl-benzenesulfonamide

A 200 mL round-bottom flask was charged with2-bromo-5-chloro-pyridin-3-ylamine (10.4 g, 50.0 mmol),4-tert-butyl-benzenesulfonyl chloride (20.0 g, 85.0 mmol), and pyridine(38 mL). The resultant solution was heated to 70° C. and stirredovernight. The following day, the pyridine was removed by removed invacuo and 30 mL THF (tetrahydrofuran) and 100 mL 4.0 N NaOH were addedand the reaction was stirred at 60° C. overnight. The organics weresubsequently removed in vacuo and the residues were diluted with 400 mLwater. The small quantity of insoluble solid was removed by filtrationand the pH was adjusted to 6-7 with concentrated HCl. The resultantaqueous solution was extracted with EtOAc, washed with brine, dried overMgSO₄, and concentrated under reduced pressure to afford the desiredsulfonamide (13.4 g) in 66% yield: MS (ES) M+H expected 403.0, found403.1.

General Procedure B

ExampleN-(2-Bromo-4-chloro-phenyl)-4-tert-butyl-N-methoxymethyl-benzenesulfonamide

To a solution ofN-(2-bromo-4-chloro-phenyl)-4-tert-butyl-benzenesulfonamide (1.00 g,2.49 mmol) and K₂CO₃ (1.72 g, 12.4 mmol) in 8 mL anhydrous THF was addedchloromethyl methyl ether (299 mg, 3.73 mmol). The resultantheterogeneous solution was stirred for 60 minutes at ambient temperatureand the solids were subsequently removed via filtration. The filtratewas subsequently concentrated in vacuo and the residue was dissolved inEtOAc. The organics were washed with saturated Na₂CO₃, dried over MgSO₄,and evaporated in vacuo. The resultant residue was then purified viaautomated silica gel chromatography to afford the desired protectedsulfonamide: MS (ES) M+H expected 446.0, found 446.0.

ExampleN-(2-Bromo-5-chloro-pyridin-3-yl)-4-tert-butyl-N-methoxymethyl-benzenesulfonamide

To a solutionN-(2-bromo-5-chloro-pyridin-3-yl)-4-tert-butyl-benzenesulfonamide (12.0g, 35.0 mmol) and K₂CO₃ (24.0 g, 170 mmol) in 80 mL anhydrous THF wasadded chloromethyl methyl ether (4.0 mL, 52.7 mmol). The resultantheterogeneous solution was stirred for 60 minutes at ambient temperatureand the solids were subsequently removed via filtration. The filtratewas then removed in vacuo and the residue was dissolved in EtOAc. Theorganics were washed with saturated Na₂CO₃, dried over MgSO₄, andevaporated in vacuo to generate a brownish oil. The oil was finallytriturated with hexanes and the resultant solid filtered to produce thedesired product as a light yellowish solid (11.5 g, 86% yield): MS (ES)M+H expected 447.0, found 447.0.

General Procedure D

Example4-tert-Butyl-N-(4-chloro-2-[1,2,3]triazolo[4,5-b]pyridine-1-yl-phenyl)-benzenesulfonamide

A 4 mL scintillation vial was charged with4-tert-butyl-N-(4-chloro-2-iodo-phenyl)-benzenesulfonamide (84 mg, 0.19mmol), 4-azabenzotriazole (29 mg, 0.22 mmol), CuI (3 mg, 0.014 mmol),Cs₂CO₃ (127 mg, 0.39 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine(5 mg, 0.04 mmol), and dioxane (500 μL). The reaction was heated to 90°C. and stirred overnight. The following day, the volatiles were removedin vacuo. The residue was subsequently diluted in EtOAc and washed withsaturated NH₄Cl (aq). The organic layer was then concentrated in vacuoand the residue purified by preparative TLC (thin-layer chromatography)to afford4-tert-butyl-N-(4-chloro-2-[1,2,3]triazolo[4,5-b]pyridine-1-yl-phenyl)-benzenesulfonamide:MS (ES) M+H expected 442.1, found 442.0.

Example4-tert-Butyl-N-(5-chloro-2-pyrazolo[4,3-b]pyridin-1-yl-pyridin-3-yl)-benzenesulfonamide

A solution of N-(2-bromo-5-chloro-pyridin-3-yl)-4-tert-butyl-benzenesulfonamide (226 mg, 0.559 mmol), 1H-pyrazolo[4,3-b]pyridine (100 mg,0.839 mmol), trans-N,N′-dimethyl-cyclohexane-1,2-diamine (18 μL, 0.112mmol), copper iodide (22 mg, 0.112 mmol), and cesium carbonate (383 mg,1.17 mmol) in 2 mL of N,N-dimethylacetamide was heated at 130° C. for 2hours. Ethyl acetate and water were added and the layers were separated.The organic layer was washed with brine, dried over magnesium sulfate,filtered, and concentrated in vacuo. The crude reside was subsequentlypurified by flash column chromatography (0-100% ethyl acetate inhexanes) to afford4-tert-butyl-N-(5-chloro-2-pyrazolo[4,3-b]pyridin-1-yl-pyridin-3-yl)-benzenesulfonamide: MS (ES) M+H expected 442.1, found 442.0.

General Procedure E

Example1-[2-(4-tert-Butyl-benzenesulfonylamino)-5-chloro-phenyl]-1H-pyrazole-4-carboxylicacid amide

1-[2-(4-tert-butyl-benzenesulfonylamino)-5-chloro-phenyl]-1H-pyrazole-4-carboxylicacid ethyl ester (synthesized according to general procedure D, 55 mg,0.119 mmol) and 1 mL of ammonium hydroxide were stirred at 70° C. for 18hours. The resultant solution was partitioned between saturated sodiumbicarbonate and dichloromethane, and the aqueous layer extracted withdichloromethane. The combined organic layers were dried over magnesiumsulfate, filtered, and concentrated in vacuo. The crude product wassubsequently purified by flash column chromatography (0-100% ethylacetate in hexanes) to yield1-[2-(4-tert-butyl-benzenesulfonylamino)-5-chloro-phenyl]-1H-pyrazole-4-carboxylicacid amide: MS (ES) M+H expected 433.1, found 433.0.

Example1-[3-(4-tert-Butyl-benzenesulfonylamino)-5-chloro-pyridin-2-yl]-1H-pyrazole-4-carboxylicacid dimethylamide

A 25 mL scintillation vial was charged with1-[3-(4-tert-butyl-benzenesulfonylamino)-5-chloro-pyridin-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (synthesized according to general procedure D, 93 mg,0.2 mmol), NaOH (2 mL, 1.0 M solution in water), and THF (3 mL). Thevial was sealed and stirred at 80° C. for 16 hours. The reactionsolution was subsequently neutralized to pH=5 with glacial acetic acid.The mixture was extracted with ethyl acetate (2×10 mL) and the combinedorganics were concentrated in vacuo. The crude product was subsequentlydissolved in 2 mL of THF in a 25 mL scintillation vial. To the resultantsolution was added with dimethylamine (0.2 mL, 2.0 M in THF),1-propanephosphonic anhydride solution (184 mg, 50% solution in ethylacetate), and triethylamine (41 mg, 0.4 mmol). The vial was sealed andstirred at ambient temperature for 1 hour. The volatiles were thenevacuated in vacuo and the residue was purified via preparative HPLC toafford1-[3-(4-tert-butyl-benzenesulfonylamino)-5-chloro-pyridin-2-yl]-1H-pyrazole-4-carboxylicacid dimethylamide as a white powder: MS (ES) M+H expected 462.1, found462.0.

General Procedure F

Example 4-Chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenylamine

Step 1: 4-Chloro-2-fluoro-1-nitrobenzene (25 g, 142 mmol) and1H-[1,2,3]triazolo[4,5-b]pyridine (18.8 g, 157 mmol) were slurried inDMF (50 mL) in a 200 mL round-bottom flask fitted with a magnetic stirbar. Potassium carbonate (29.5 g, 214 mmol) was added to the mixture andit was then heated while stirring in a 60° C. oil bath under N₂. LCMSanalysis after two hours indicated complete consumption of thenitrobenzene and two different isomeric forms of the desired product.Water (250 mL) was subsequently added in a steady stream to the rapidlystirring mixture to precipitate the crude product. The resultantprecipitate was collected by vacuum filtration and washed with 2×100 mLwater.

The resultant damp filter was slurried with 50 mL toluene and the solidscollected by vacuum filtration. This action was repeated threeadditional times and then the resultant solid was dried in vacuo toafford 21.6 g (55% yield)1-(5-chloro-2-nitrophenyl)-1H-[1,2,3]triazolo[4,5-b]pyridine as anoff-white solid.

Step 2: 1-(5-Chloro-2-nitrophenyl)-1H-[1,2,3]triazolo[4,5-b]pyridine (10g, 36.3 mmol) was dissolved in 200 mL concentrated HCl in a 1 Lround-bottom flask fitted with a magnetic stir bar. Iron powder (4.2 g,74.4 mmol) was added in portions to the rapidly stirring solution. Theresultant thick yellow slurry was allowed to stir overnight until novisible metallic iron was observed in the reaction vessel. The followingday, LCMS analysis indicated complete reduction to the aniline. Themixture was subsequently transferred to a 500 mL Buchner funnel, withthe assistance of a small amount of concentrated HCl to rinse out theremaining slurry from the reaction vessel, and the insoluble materialwas collected by vacuum filtration. The filter cake was then stirredinto a thick paste with water (15 mL) and the solids collected by vacuumfiltration. The material was again stirred in 15 mL water and filtered,the mother liquors were discarded, and the solid material dried invacuo. The resultant light brown solid was slurried in 50 mL of 1:1(v/v) EtOAc:acetonitrile and heated to the boiling point with a heatgun. The mixture was allowed to cool to room temperature and the solidswere collected by vacuum filtration. The solids were subsequently washedwith a small amount of 1:1 EtOAc:acetonitrile and dried in vacuo togenerate 7.5 g 4-chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenylamine(light grey solid, 84% yield): MS (ES) M+H expected 246.0, found 246.0.

Example1-[3-(4-tert-Butyl-benzenesulfonylamino)-5-chloro-pyridin-2-yl]-1H-pyrazole-4-carboxylicacid

A 25 mL scintillation vial was charged with1-[3-(4-tert-butyl-benzenesulfonylamino)-5-chloro-pyridin-2-yl]-1H-pyrazole-4-carboxylicacid ethyl ester (synthesized according to general procedure D, 93 mg,0.2 mmol), NaOH (2 mL, 1.0 M solution in water), and THF (3 mL). Thevial was sealed and stirred at 80° C. for 16 hours. The reactionsolution was subsequently neutralized to pH=5 with glacial acetic acid.The mixture was extracted with ethyl acetate (2×10 mL) and the combinedorganics were concentrated in vacuo. The resultant residue was purifiedvia preparative HPLC to afford1-[3-(4-tert-butyl-benzenesulfonylamino)-5-chloro-pyridin-2-yl]-1H-pyrazole-4-carboxylicacid as a white powder: MS (ES) M+H expected 435.1, found 435.0.

General Procedure G

ExampleN-(4-Chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-4-(1,1-dimethyl-propyl)-benzenesulfonamide

A 4 mL scintillation vial was charged with4-chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenylamine (100 mg, 0.363mmol), 4-(1,1-dimethyl-propyl)-benzenesulfonyl chloride (98 g, 0.399mmol), and pyridine (1 mL). The resultant solution was stirred 4 hoursat 80° C. and then partitioned with EtOAc/1 M HCl. The organics weresubsequently washed with 1 M HCl, saturated aqueous sodium bicarbonate,and brine; dried over anhydrous sodium sulfate; and removed in vacuo.The resultant residue was then purified via automated silica gelchromatography to afford the desired sulfonamide: MS (ES) M+H expected456.2, found 456.3.

ExampleN-[2-(4-Amino-pyrazol-1-yl)-5-chloro-pyridin-3-yl]-4-tert-butyl-benzenesulfonamide

Step 1: A solution ofN-(2-bromo-5-chloro-pyridin-3-yl)-4-tert-butyl-benzene sulfonamide (534mg, 1.32 mmol), 4-nitropyrazole (224 mg, 1.98 mmol),trans-N,N′-dimethyl-cyclohexane-1,2-diamine (42 μL, 0.264 mmol), copperiodide (51 mg, 0.264 mmol), and cesium carbonate (903 mg, 2.77 mmol) in5 mL of N,N-dimethylacetamide was heated at 130° C. for 2 hours. Ethylacetate and water were added and the layers were separated. The organiclayer was washed with brine, dried over magnesium sulfate, filtered, andconcentrated in vacuo. The crude reside was subsequently purified byflash column chromatography (0-100% ethyl acetate in hexanes) to afford4-tert-butyl-N-[5-chloro-2-(4-nitro-pyrazol-1-yl)-pyridin-3-yl]-benzenesulfonamideas a white solid.

Step 2: To a solution of4-tert-butyl-N-[5-chloro-2-(4-nitro-pyrazol-1-yl)-pyridin-3-yl]-benzenesulfonamide(100 mg, 0.229 mmol) in 2 mL of ethanol was added 10% Pd/C and theheterogeneous solution was stirred under an atmosphere of hydrogen.After two hours, the reaction was filtered through celite andconcentrated in vacuo. The crude reside was subsequently purified byflash column chromatography (0-100% ethyl acetate in hexanes) to affordN-[2-(4-amino-pyrazol-1-yl)-5-chloro-pyridin-3-yl]-4-tert-butyl-benzenesulfonamide as a white solid: MS (ES) M+H expected 406.1, found 406.0.

General Procedure H

Example1-[2-(4-tert-Butyl-benzenesulfonylamino)-5-chloro-phenyl]-1H-[1,2,3]triazole-4-carboxylicacid amide

A 4 mL scintillation vial was charged with1-[2-(4-tert-butyl-benzenesulfonylamino)-5-chloro-phenyl]-1H-[1,2,3]triazole-4-carboxylicacid ethyl ester (synthesized according to general procedure G, 10 mg,0.02 mmol) and 2 M NH₃ in EtOH (1 mL). The reaction was heated to 100°C. and stirred overnight. The following day, the volatiles were removedin vacuo and the residue was purified by preparative TLC chromatographyto afford1-[2-(4-tert-butyl-benzenesulfonylamino)-5-chloro-phenyl]-1H-[1,2,3]triazole-4-carboxylicacid amide: MS (ES) M+H expected 434.1, found 434.0.

ExampleN-{1-[3-(4-tert-Butyl-benzenesulfonylamino)-5-chloro-pyridin-2-yl]-1H-pyrazol-4-yl}-acetamide

A solution ofN-[2-(4-amino-pyrazol-1-yl)-5-chloro-pyridin-3-yl]-4-tert-butyl-benzenesulfonamide(20 mg, 0.049 mmol), acetyl chloride (3.5 μL, 0.049 mmol), andtriethylamine (14 μL, 0.099 mmol) were stirred at room temperature for 1hour. The reaction was concentrated in vacuo, followed by the additionof dicholoromethane (1 mL) and tetrabutylammonium fluoride (0.4 mL, 1.0M in THF). The reaction was stirred for 2 hours at room temperature andthen the crude mixture was partitioned with saturated sodiumbicarbonate. The aqueous phase was subsequently extracted withdichloromethane and the combined organic layers dried over magnesiumsulfate, filtered, and concentrated in vacuo. The crude product waspurified by flash column chromatography (0-100% ethyl acetate inhexanes) to affordN-{1-[3-(4-tert-butyl-benzenesulfonylamino)-5-chloro-pyridin-2-yl]-1H-pyrazol-4-yl}-acetamide:MS (ES) M+H expected 448.1, found 448.0.

General Procedure I

Example1-[2-(4-tert-Butyl-benzenesulfonylamino)-5-chloro-phenyl]-1H-[1,2,3]triazole-4-carboxylicacid

A 4 mL scintillation vial was charged with1-[2-(4-tert-butyl-benzenesulfonylamino)-5-chloro-phenyl]-1H-[1,2,3]triazole-4-carboxylicacid ethyl ester (synthesized according to general procedure G, 10 mg,0.02 mmol) and 3 M NaOH (aq)/THF (1:3) (1 mL). The reaction was heatedto 60° C. and stirred overnight. The following day, the volatiles wereremoved in vacuo and the residue was purified by preparative TLC toafford1-[2-(4-tert-butyl-benzenesulfonylamino)-5-chloro-phenyl]-1H-[1,2,3]triazole-4-carboxylicacid: MS (ES) M+H expected 435.1, found 435.0.

Example4-tert-Butyl-N-[5-chloro-2-(4-oxazol-2-yl-pyrazol-1-yl)-pyridin-3-yl]-benzenesulfonamide

A 25 mL scintillation vial was charged with1-[3-(4-tert-butyl-benzenesulfonylamino)-5-chloro-pyridin-2-yl]-1H-pyrazole-4-carboxylicacid (87 mg, 0.2 mmol), oxalyl chloride (2 mL, 1.0 M solution indichloromethane), and dichloromethane (3 mL). The mixture was stirred atroom temperature for 2 hours, the volatiles removed in vacuo, and theresidue further dried at reduced pressure for 4 hours. The scintillationvial containing the crude acid chloride was subsequently charged with1H-1,2,3-triazole (34 mg, 0.5 mmol), K₂CO₃ (138 mg, 1.0 mmol), andsulfolane (2 mL). The vial was sealed and stirred at 80° C. for 16hours. The reaction solution was neutralized to pH=7 with glacial aceticacid. The mixture was extracted with ethyl acetate (2×10 mL) and thecombined organics were concentrated in vacuo. The residue was purifiedvia preparative HPLC to afford4-tert-butyl-N-[5-chloro-2-(4-oxazol-2-yl-pyrazol-1-yl)-pyridin-3-yl]-benzenesulfonamideas a white powder: MS (ES) M+H expected 458.1, found 458.0.

General Procedure J

ExampleN-[2-(4-Amino-[1,2,3]triazolo[4,5-c]pyridin-1-yl)-4-chloro-phenyl]-4-tert-butyl-benzenesulfonamide

A 4 mL scintillation vial was charged with4-tert-butyl-N-[4-chloro-2-(4-chloro-[1,2,3]triazolo[4,5-c]pyridin-1-yl)-phenyl]-benzenesulfonamide(synthesized according to general procedure G, 20 mg, 0.042 mmol) and 2M NH₃ in EtOH (2 mL). The reaction was sealed and heated to 120° C. for18 hours. The EtOH was then removed in vacuo and the resultant residuewas purified by preparative TLC to affordN-[2-(4-amino-[1,2,3]triazolo[4,5-c]pyridin-1-yl)-4-chloro-phenyl]-4-tert-butyl-benzenesulfonamide:MS (ES) M+H expected 457.1, found 457.0.

General Procedure K

Example4-tert-Butyl-N-(4-cyano-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-benzenesulfonamide

A 4 mL scintillation vial was charged withN-(4-bromo-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-4-tert-butyl-benzenesulfonamide(synthesized according to general procedure G, 20 mg, 0.04 mmol),Zn(CN)₂ (8 mg, 0.06 mmol), Pd(dppf)Cl₂ (4 mg, 0.005 mmol), TEA (10 μL,0.07 mmol), and toluene (300 μL). The reaction was sealed and heated to100° C. for 18 hours. The solvent was subsequently removed in vacuo andthe resultant residue was purified by preparative TLC to afford4-tert-butyl-N-(4-cyano-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-benzenesulfonamide:MS (ES) M+H expected 433.1, found 433.0.

General Procedure L

Example4-tert-Butyl-N-(3,4-dichloro-2-pyrazol-1-yl-phenyl)-benzenesulfonamide

A 25 mL scintillation vial was charged with4-tert-butyl-N-(4-chloro-2-pyrazol-1-yl-phenyl)-benzenesulfonamide(synthesized according to general procedure D, 78 mg, 0.2 mmol),N-chlorosuccinimide (67 mg, 0.5 mmol), benzoyl peroxide (2.4 mg, 0.01mmol), and carbon tetrachloride (4 mL). The vial was sealed and stirredfor 18 hours at 80° C. The resultant solution was partitioned betweenethyl acetate and water and the combined organics were washed with 1 NHCl, saturated sodium bicarbonate, and brine; dried over magnesiumsulfate; filtered; and concentrated in vacuo. The crude product wassubsequently purified by flash column chromatography (10-100% ethylacetate in hexanes) followed by preparative HPLC (10-90% gradient ofMeCN:water) to afford the title compound as a white solid: MS (ES) M+Hexpected 424.1, found 424.1.

General Procedure M

Example4-tert-Butyl-N-[4-chloro-2-(4,5,6,7-tetrahydro-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-phenyl]-benzenesulfonamide

A 250 mL pressure vessel was charged with4-tert-butyl-N-(4-chloro-2-[1,2,3]triazolo[4,5-b]pyridine-1-yl-phenyl)-benzenesulfonamide(synthesized according to general procedure G, 100 mg, 0.23 mmol), PtO₂(50 mg, 0.22 mmol), and MeOH (20 mL). The pressure vessel was placedunder 60 p.s.i. of H₂ and agitated for 8 hours. The reaction mixture wassubsequently filtered through celite, concentrated in vacuo, andpurified by preparative TLC to afford4-tert-butyl-N-[4-chloro-2-(4,5,6,7-tetrahydro-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-phenyl]-benzenesulfonamide:MS (ES) M+H expected 446.1, found 446.1.

General Procedure N

Example4-tert-Butyl-N-[4-chloro-2-(4-methyl-4,5,6,7-tetrahydro-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-phenyl]-benzenesulfonamide

A 4 mL scintillation vial was charged with4-tert-butyl-N-[4-chloro-2-(4,5,6,7-tetrahydro-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-phenyl]-benzenesulfonamide(synthesized according to general procedure M, 11 mg, 0.025 mmol), H₂CO(37% in H₂O, 3 mg, 0.037 mmol), and HCO₂H (100 μL). The vial was sealedand heated to 100° C. for 1 hour. The solvent was subsequently removedin vacuo and the residue purified by preparative TLC to afford4-tert-butyl-N-[4-chloro-2-(4-methyl-4,5,6,7-tetrahydro-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-phenyl]-benzenesulfonamide:MS (ES) M+H expected 460.2, found 460.0.

General Procedure O

Example4-tert-Butyl-N-[4-chloro-2-(4-methanesulfonyl-4,5,6,7-tetrahydro-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-phenyl]-benzenesulfonamide

A 4 mL scintillation vial was charged with4-tert-butyl-N-[4-chloro-2-(4,5,6,7-tetrahydro-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-phenyl]-benzenesulfonamide(synthesized according to general procedure M, 13 mg, 0.029 mmol),MeSO₂Cl (5 mg, 0.04 mmol), and pyridine (500 μL). The reaction wasstirred for 1 hour. The solvent was subsequently removed in vacuo andthe residue purified by preparative TLC to afford4-tert-butyl-N-[4-chloro-2-(4-methanesulfonyl-4,5,6,7-tetrahydro-[1,2,3]triazolo[4,5-b]pyridin-1-yl)-phenyl]-benzenesulfonamide:MS (ES) M+H expected 524.1, found 524.0.

General Procedure P

Example4-tert-Butyl-N-[4-chloro-2-(5-isopropyl-[1,2,3]triazol-1-yl)-phenyl]-benzenesulfonamide

Step 1: A 30 mL scintillation vial was charged with2-azido-4-chloro-1-nitrobenzene (200 mg, 1.0 mmol) and 0.75 M3-methyl-1-butynylmagnesium chloride in THF (1.6 mL, 1.2 mmol; preparedby mixing 3-methyl-1-butyne (120 μL, 1.2 mmol) and iPrMgCl (1.5 mL, 1.0M in THF) at room temperature, heating to 40° C. for 30 minutes thencooling to room temperature). The reaction was allowed to stir at roomtemperature for 1 hour after which the reaction was quenched with SiO₂and the solvent removed. The product (adsorbed to SiO₂) was then loadedon a SiO₂ column and purified to give1-(5-chloro-2-nitro-phenyl)-5-isopropyl-1H-[1,2,3]triazole.

Step 2: The product was then reduced (according to general procedure F,step 2) and sulfonylated (according to general procedure G) to afford4-tert-butyl-N-[4-chloro-2-(5-isopropyl-[1,2,3]triazol-1-yl)-phenyl]-benzenesulfonamide:MS (ES) M+H expected 433.2, found 433.1.

General Procedure Q

Example4-tert-Butyl-N-[4-chloro-2-(5-dimethylaminomethyl-[1,2,3]triazol-1-yl)-phenyl]-benzenesulfonamide

A 30 mL scintillation vial was charged with4-tert-butyl-N-[4-chloro-2-(5-diethoxymethyl-[1,2,3]triazol-1-yl)-phenyl]-benzenesulfonamide(synthesized according to general procedure Q, 1.0 g, 2.0 mmol) andAc₂O/pyridine (1:2 v/v, 6 mL), and stirred at room temperature for 4hours. The reaction mixture was subsequently diluted with Et₂O andwashed with 1 M HCl, saturated NaHCO₃, and brine. The combined organicswere then dried over Na₂SO₄ and concentrated in vacuo. The resultantproduct (35 mg, 0.075 mmol) and dimethyl amine (80 μL, 2.0 M in THF)were combined in a 4 mL scintillation vial and stirred for 30 minutes.NaBH(OAc)₃ (32 mg, 0.17 mmol) was then added and the reaction wasstirred for 12 hours at room temperature. The reaction mixture wassubsequently diluted with Et₂O, washed with 1 M HCl, and the combinedorganics were purified by preparative TLC to generate4-tert-butyl-N-[4-chloro-2-(5-dimethylaminomethyl-[1,2,3]triazol-1-yl)-phenyl]-benzenesulfonamide:MS (ES) M+H expected 448.2, found 448.4.

General Procedure R

ExampleN-(4-Chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-3-fluoro-4-morpholin-4-yl-benzenesulfonamide

4-Bromo-N-(4-chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-3-fluoro-benzensulfonamide(synthesized according to general procedure G, 180 mg, 0.37 mmol) wasdissolved in 3 ml of anhydrous dimethylformamide under an atmosphere ofnitrogen. To this mixture was added morpholine (161 mg, 1.85 mmol),2,2′-bis(diphenylphosphine)-1,1′-binaphthyl (BINAP) (34 mg, 0.055 mmol),potassium phosphate tribasic monohydrate (511 mg, 2.22 mmol), andtris(dibenzylideneacetone) dipalladium(0) (Pd₂(dba)₃) and the resultantmixture was heated at 80° C. overnight. The following day, the reactionmixture was partitioned with a saturated solution of sodium bicarbonateand dichloromethane and the aqueous layer was extracted three times withdichloromethane. The combined organics were subsequently dried overmagnesium sulfate, concentrated in vacuo, and purified by reverse phaseHPLC, followed by silica gel chromatography employing ethylacetate:hexanes (1:1), to afford 80 mg of the desired product as a whitepowder: MS (ES) M+H expected 489.1, found 489.0.

General Procedure S

Example4-tert-Butyl-N-{4-chloro-2-[4-(1-hydroxy-1-methyl-ethyl)-pyrazol-1-yl]-phenyl}-benzenesulfonamide

A 4 mL scintillation vial was charged with1-[2-(4-tert-butyl-benzenesulfonylamino)-5-chloro-phenyl]-1H-pyrazole-4-carboxylicacid ethyl ester (synthesized from general procedure D, 100 mg, 0.22mmol) in 0.5 mL of anhydrous THF and cooled to 0° C. under a nitrogenatmosphere. To this solution was added of methyl magnesium bromide (0.36mL, 3.0 M in Et₂O) and the reaction was allowed to slowly warm toambient temperature. Upon complete consumption of the starting material(via LCMS), the reaction was quenched by the addition of an NH₄Clsolution. The solvent was subsequently removed in vacuo and the residuewas purified via preparative HPLC to afford4-tert-butyl-N-{4-chloro-2-[4-(1-hydroxy-1-methyl-ethyl)-pyrazol-1-yl]-phenyl}-benzenesulfonamideas a white powder: MS (ES) M+H expected 448.1, found 448.1.

General Procedure T

Example4-tert-Butyl-N-[4-chloro-2-(1H-pyrazolo[3,4-b]pyridin-3-yl)-phenyl]-benzenesulfonamide

4-tert-butyl-N-(4-chloro-2-iodo-phenyl)-benzenesulfonamide (100 mg, 0.22mmol), 3-iodo-1H-pyrazolo[3,4-b]pyridine (71 mg, 0.29 mmol),bis(triphenylphosphine)Pd(II)dichloride (20 mg, 0.03 mmol), andhexamethylditin (70 μL, 0.33 mmol) were suspended in 0.7 mL of dioxaneand heated to 100° C. for 24 hours in a sealed 4 mL scintillation vial.The black crude residue obtained was purified by preparative TLC toafford4-tert-butyl-N-[4-chloro-2-(1H-pyrazolo[3,4-b]pyridin-3-yl)-phenyl]-benzenesulfonamide:MS (ES) M+H expected 441.1, found 441.0.

General Procedure U

Example N-(2-Boranyl-4-chloro-phenyl)-4-tert-butyl-benzenesulfonamide

Step 1: A 100 mL round bottom flask was charged with2-bromo-4-chloroaniline (20.6 g, 100 mmol), tricyclohexylphosphine(Cy₃P)(0.73 g, 2.02 mmol), palladium acetate (0.115 g, 0.505 mmol),4,4,5,5,4′,4′,5′,5′-Octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (25.4 g,100 mmol), triethylamine (1.22 g, 120 mmol), dioxane (200 mL). Thereaction was stirred at 85° C. for 18 hours under nitrogen. The reactionmixture was quenched by adding 200 mL of water and then extracted withethyl acetate (100 mL, 3 times). The organic layers were combined anddried over Na₂SO₄ overnight. Solid was filtered off and the filtrate wasconcentrated to dryness. The crude product was purified by flashchromotagraph to yield 13.2 g of product as colorless solid. MS (ES) M+Hexpected 140.1, found 140.1.

Step 2: A 100 mL round-bottom flask was charged with2-boranyl-4-chloro-phenylamine (1.1 g, 7.9 mmol) and 4-tert-butylbenzenesulfonyl chloride (2.7 g, 11.6 mmol). The flask was evacuated andpurged with nitrogen, followed by the addition of pyridine (20 mL). Thehomogeneous light purple solution was stirred 4 hours, and then pouredonto a rapidly stirring cold slurry of 6 M HCl (66 mL) (formed byplacing the acidic solution in acetonic dry ice). The resultantprecipitated sulfonamide was filtered, washed thoroughly with 10% HCl,and dried in vacuo to afford purplish solid. The crude product waspurified by flash chromatograph to yield 1.3 g of product as colorlesssolid: MS (ES) M+H expected 336.5, found 336.5.

General Procedure V

Example4-tert-Butyl-N-[4-chloro-2-(1H-indazol-3-yl)-phenyl]-benzenesulfonamide

A 25 mL scintillation vial was charged withN-(2-boranyl-4-chloro-phenyl)-4-tert-butyl-benzenesulfonamide (90 mg,0.27 mmol), tris(dibenzylideneacetone)dipalladium (18 mg, 0.02 mmol),2-dicyclohexylphosphino-2′, 4′, 6′-triisopropylbiphenyl (24 mg, 0.05mmol), 3-iodo-1H-indazole (65 mg, 0.27 mmol), saturated aqueous sodiumbicarbonate (1 mL), and tetrahydrofuran (1.5 mL). The reaction wasstirred at 80° C. under nitrogen overnight. The following day, thereaction was cooled to room temperature and diluted with 10 mL of ethylacetate. The solution was subsequently washed with saturated aqueousNaHCO₃ and brine, and then concentrated to dryness. The crude productwas purified by flash chromatograph to yield 23 mg of product: MS (ES)M+H expected 441.1, found 441.1.

General Procedure W

ExampleN-(4-Chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-4-{1-[(E)-hydroxyimino]-ethyl}benzenesulfonamide

A 4 mL vial was charged with4-acetyl-N-(4-chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-benzenesulfonamide(synthesized according to general procedures F and G, 100 mg, 0.23mmol), hydroxylamine hydrochloride (49 mg, 0.70 mmol), and 2 mL THF. Theresultant slurry was mixed well, then titanium ethoxide (98 μL, 47 mmol)was added and the mixture heated to 60° C. overnight. The reactionmixture was subsequently diluted with ˜2 mL of acetonitrile/H₂O andpurified by reversed phase HPLC to affordN-(4-chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-4-{1-[(E)-hydroxyimino]-ethyl}benzenesulfonamide:MS (ES) M+H expected 443.0, found 443.0.

General Procedure X

Example4-(1-Amino-ethyl)-N-(4-chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-benzenesulfonamide

A 4 mL vial was charged with4-acetyl-N-(4-chloro-2-,[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-benzenesulfonamide(synthesize according to general procedures F and G, 100 mg, 0.23 mmol),7 M NH₃ in MeOH (100 μL, 0.70 mmol, and 2 mL THF. The resulting slurrywas stirred well, the titanium ethoxide (98 μL, 47 mmol) was added andthe mixture heated to 60°C. for three hours. Sodium cyanoborohydride (22mg, 0.35 mmol) and acetic acid (5 drops) were then added and the mixturewas maintained at 60 ° C. overnight. The reaction mixture was dilutedwith ˜2 mL of acetonitrile/H₂0 and purified by reversed phase HPLC toafford 4-(1-amino-ethyl)-N-(4-chloro-2-[1,2,3]triazolo[4,5-]pyridin-1-phenyl) -benzensulfonamide: MS (ES) M+H expected428.0, found 428.0

General Procedure Y

Example N-(4-Chloro-2[1,2,3]trazolo[4,5-b]pyridin-1-yl-phenyl)-4-(1-hydroxy-1-methyl-ethyl)-benzene-sulfonamide

Step 1:4-Chloro-2-fluoro-1-nitrobenzene (25 g, 142 mmol) and1H-[1,2,3]triazolo[4,5-b]pyridine (18.8 g, 157 mmol) were slurried inDMF (50 mL) in a 200 mL round-bottom flask fitted with a magnetic stirbar. Potassium carbonate (29.5 g, 214 mmol) was added to the mixture andit was then heates while stirring in a 60°C. oil bath under N₂. LCMSanalysis after two hours indicated complete consumption of thenitrobenzene and two different isomeric forms of the desired product.Water (250 mL) was subsequently added in a steady stream to the rapidlystirring mixture to precipitate the crude product. The resultantprecipitate was collected by vacuum filtration and washed twice with 100mL water. The resultant damp filter was slurried with 50 mL toluene andthe solids collected by vacuum filtration. This action was repeatedthree additional times and then the resultant solid was dried in vacuoto afford 21.6 g (55% yield) 1-(5-chloro-2-nitrophenyl)-1H-[1,2,3]triazolo[4,5-b]pyridine as an off-white solid.

Step 2: 1-(5-Chloro-2-nitrophenyl)-1H-[1,2,3]triazolo[4,5-b]pyridine (10g, 36.3 mmol) was dissolved in 200 mL concentrated HCl in a 1 Lround-bottom flask fitted with a magnetic stir bar. Iron powder (4.2 g,74.4 mmol) was added in portions to the rapidly stirring solution. Theresultant thick yellow slurry was allowed to stir overnight until novisible metallic iron was observed in the reaction vessel. The followingday, LCMS analysis indicated complete reduction to the aniline. Themixture was subsequently transferred to a 500 mL Buchner funnel, withthe assistance of a small amount of concentrated HCl to rinse out theremaining slurry from the reaction vessel, and the insoluble materialwas collected by vacuum filtration. The filter cake was then stirredinto a thick paste with water (15 mL) and the solids collected by vacuumfiltration. The material was again stirred in 15 mL water and filtered,the mother liquors were discarded, and the solid material dried invacuo. The resultant light brown solid was slurried in 50 mL of 1:1(v/v) EtOAc:acetonitrile and heated to the boiling point with a heatgun. The mixture was allowed to cool to room temperature and the solidswere collected by vacuum filtration. The solids were subsequently washedwith a small amount of 1:1 EtOAc:acetonitrile and dried in vacuo togenerate 7.5 g 4-chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenylamine(light grey solid, 84% yield).

Step 3: To 4-chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenylamine(33.9 g, 138.0 mmol) was added pyridine (170 mL), followed by4-acetylbenzenesulfonyl chloride (45.3 g, 207 mmol) at room temperature.Upon stirring for 10 minutes, the flask was cooled to 0° C. and CH₃SO₂Cl(8.0 mL, 103.5 mmol) was added dropwise under a nitrogen atmosphere. Theresultant reaction mixture was allowed to warm to room temperature over8 hours with stirring. 5 N NaOH (200 mL) was subsequently added to thereaction mixture and stirred at 75° C. for 12 hours to hydrolyze thebis-sulfonamide. The hot reaction mixture was then slowly poured into 2N HCl (500 mL) with efficient stirring. The solution was stirred for 15minutes and the precipitated solid was isolated via filtration through asintered-glass funnel. The solid was then washed with water (1000 mL)and heptanes (1000 mL), and then dried at 75° C. in a vacuum oven for 12hours to provide the desired sulfonamide as yellow solid (56.5 g) in 96%yield.

A 1-L round-bottom flask was charged with the resultant ketone (54.2 g,127 mmol). The solid was then dissolved in 500 mL anhydrous THF(tetrahydrofuran) and the solution was cooled to −40° C. To the rapidlystirring solution was added 3.0 M MeMgBr (169 mL, 508 mmol) and thereaction was warmed to −20° C. and stirred for 2 hours. Upon consumptionof starting material, the reaction was quenched with acetone (40 mL) at−20° C. and then warmed to ambient temperature. An additional 100 mLwater was added to the reaction and it was concentrated to a primarilyaqueous heterogeneous syrup. The syrup was subsequently poured onto 500mL 1 N HCl and stirred for 1 hour at room temperature. The resultantprecipitate was filtered and the solid was washed with water (1 L) andheptanes (750 mL), and then dried at 70° C. overnight in a vacuum ovento provide 54.5 g of the crude product as a light brown solid. The solidwas subsequently dissolved in 1.3 L 85% MeCN/water at reflux and thesolution then cooled to ambient temperature. To the resultant solutionwas added activated charcoal (28 g) and the solution was stirred 5minutes. The heterogeneous suspension was then filtered through CELITE®,the filter cake washed thoroughly with MeCN, and the filtrateconcentrated in vacuo to afford 46.3 g of a slightly yellowish solid.The resultant solid was dissolved in refluxing 85% MeCN/water (712 mL),filtered (while hot) to remove a minimal quantity of insoluble material,and then cooled slowly to room temperature to enable crystallization toproceed. The flask was allowed to sit 4 hours at ambient temperature andthen stored overnight in a refrigerator. The following day, the solidwas collected via filtration and then washed with MeCN. Finally, thesolid was dried at 70° C. overnight in a vacuum oven to afford thedesired dimethyl carbinol as a white solid (42.8 g, 76%): MS (ES) M+Naexpected 466.0, found 466.0.

General Procedure Z

ExampleN-(4-Chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-4-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide

DIBAL-H (diisobutylaluminium hydride)(0.71 mL, 1.0 M solution in CH₂Cl₂)was added to2-[4-(4-chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenylsulfamoyl)-phenyl]-2-methyl-propionicacid methyl ester (synthesized according to general procedures F and G,137 mg, 0.282 mmol) in CH₂Cl₂ (3 mL) at −78° C. After 1 hour, LCMSindicated a 2:1 ratio of the desired product and corresponding aldehydeintermediate. 1 N HCl (2 mL) was added to the reaction mixture, theflask was warmed to room temperature, and the solution was diluted withEtOAc (30 mL). The EtOAc layer was separated, dried (Na₂SO₄), andevaporated in vacuo. The resultant crude residue was treated with NaBH₄(30 mg, excess) in MeOH (3 mL) at room temperature for 10 minutes anddirectly purified by preparative HPLC to afford the title compound as awhite powder: MS (ES) M+H expected 458.1, found 458.0.

General Procedure AA

ExampleN-(4-Chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-4-(1-hydroxy-ethyl)-benzenesulfonamide

To4-acetyl-N-(4-chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-benzene-sulfonamide(synthesized according to general procedures F and G, 500 mg, 1.17 mmol)in MeOH (5 mL) was added NaBH₄ (144 mg, 3.81 mmol) at 0° C. and themixture was stirred for one hour at room temperature. The reactionmixture was then diluted with EtOAc (50 mL) and the organics were washedwith saturated aqueous NH₄Cl (50 mL), water (50 mL), and brine (50 mL).The organics were subsequently dried (Na₂SO₄), concentrated in vacuo,and purified by automated flash chromatography to obtain the titlecompound as foamy white solid (424 mg) in 84% yield: MS (ES) M+Hexpected 430.1, found 430.1.

General Procedure BB

ExampleN-(4-Chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-4-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)-benzenesulfonamide

To4-acetyl-N-(4-chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-benzene-sulfonamide(synthesized according to general procedures F and G, 500 mg, 1.17 mmol)was added CF₃-TMS (trifluoromethyl-trimethylsilane) (4.7 mL, 0.5 Msolution in THF), followed by TBAF (tetra-n-butylammonium fluoride)(2.34 mL, 1.0 M solution in THF) at 0° C., and the solution was stirredat room temperature for 16 hours. Both TLC and LCMS analysis indicated˜10-15% completion of reaction. The reaction mixture was diluted withEtOAc (50 mL) and the organics were washed with washed with 2 N HCl(2×25 mL), water (25 mL), and brine (25 mL). The organics weresubsequently dried (Na₂SO₄), concentrated in vacuo, and purified byautomated flash chromatography followed by preparative HPLC to affordthe title compound as a white powder: MS (ES) M+H expected 498.1, found498.0.

General Procedure CC

Example4-tert-Butyl-N-(4-chloro-2-(5-methyl-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide

4-tert-butyl-N-(4-chloro-2-(4-iodo-5-methyl1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide (synthesized accordingto general procedure P, 75 mg, 0.14 mmol) was placed in a 10 mL 2-neckflask and the flask was evacuated and purged with N₂ three times. To thesolid was added THF (0.71 mL) and the solution was lowered to −78° C.PhMgBr (0.079 mL, 1.8 M) was added to the solution and it was stirredfor 15 minutes. n-BuLi (0.069 mL, 2.0 M) was subsequently added and thereaction was stirred an additional 60 minutes. Acetone (0.042 mL, 0.57mmol) was added to the reaction and it was warmed to ambienttemperature. The solution was subsequently partitioned with EtOAc/10%HCl and the aqueous layer was extracted three times with EtOac. Thecombined organics were dried over sodium sulfate, concentrated in vacuo,and purified by HPLC to afford the desired triazole: MS (ES) M+Hexpected 405.1, found 405.4.

General Procedure DD

Example4-tert-Butyl-N-(4-chloro-2-(4-(1-hydroxyethyl)-5-methyl-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide

4-tert-butyl-N-(4-chloro-2-(4-iodo-5-methyl1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide (synthesized accordingto general procedure P, 200 mg, 0.38 mmol) was placed in a 10 mL 2-neckflask and the flask was evacuated and purged with N₂ three times. To thesolid was added THF (1.9 mL) and the solution was lowered to −78° C.PhMgBr (0.21 mL, 1.8 M) was added to the solution and it was stirred for15 minutes. n-BuLi (0.19 mL, 2.0 M) was subsequently added and thereaction was stirred an additional 30 minutes. Acetaldehyde (0.085 mL,1.5 mmol) was added to the reaction and it was warmed to 0° C. Thesolution was subsequently quenched with 10% HCl and the aqueous layerwas extracted three times with EtOac. The combined organics were driedover sodium sulfate, concentrated in vacuo, and purified by HPLC toafford4-tert-butyl-N-(4-chloro-2-(4-(1-hydroxyethyl)-5-methyl-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamideas a white solid: MS (ES) M+H expected 449.1, found 449.1.

General Procedure EE

Example4-tert-Butyl-N-(4-chloro-2-(4-ethynyl-5-methyl-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide

Step 1: A 1-dram vial was charged with4-tert-butyl-N-(4-chloro-2-(4-iodo-5-methyl1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide (synthesized accordingto general procedure P, 50 mg, 0.094 mmol), TMS acetylene (20 μL, 0.14mmol), bis(triphenylphosphine) palladium (II) dichloride (catalyticquantity), CuI (catalytic quantity), triethylamine (26 μL, 0.19 mmol),and THF (0.5 mL). The suspension was heated to 70° C. and stirred 3hours. The crude reaction was subsequently dry loaded onto silica geland purified by column chromatography to afford the desired acetylene.

Step 2: To the above TMS-protected acetylene (20 mg, 0.40 mmol) in THF(0.2 mL) was added aqueous NaOH (0.1 mL, 3 M). The solution wassubsequently heated to 60° C. and stirred for 3 hours. The crudereaction was concentrated in vacuo, dissolved in a minimal amount ofTHF, and purified by preparative TLC to produce4-tert-butyl-N-(4-chloro-2-(4-ethynyl-5-methyl-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide:MS (ES) M+H expected 429.1, found 429.3.

General Procedure FF

Example4-tert-Butyl-N-(4-chloro-2-(4-ethyl-5-methyl-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide

A pressure vessel was charged with4-tert-butyl-N-(4-chloro-2-(4-ethynyl-5-methyl-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide(synthesized according to general procedure EE, 15 mg, 0.035 mmol), PtO₂(catalytic quantity), and EtOH (10 mL). The pressure vessel was placedunder 70 p.s.i. of H₂ and agitated for 2 hours. The reaction mixture wassubsequently filtered through celite, concentrated in vacuo, andpurified by preparative TLC to afford the desired disubstitutedtriazole: MS (ES) M+H expected 433.1, found 433.4.

General Procedure GG

Example Methyl1-(2-(4-tert-butylphenylsulfonamido)-5-chlorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylate

A pressure vessel was charged with4-tert-butyl-N-(4-chloro-2-(4-iodo-5-methyl1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide (synthesized accordingto general procedure P, 100 mg, 0.19 mmol), Pd(dppf)Cl₂ (8 mg, 0.009mmol), triethylamine (52 μL, 0.38 mmol), DMF (0.8 mL), and MeOH (0.2mL). The pressure vessel was placed under 50 p.s.i. of CO at 90° C. andstirred for 10 hours. The reaction mixture was subsequently concentratedin vacuo and purified by column chromatography to afford the desireddisubstituted triazole: MS (ES) M+H expected 463.1, found 463.4.

General Procedure HH

Example4-tert-Butyl-N-(4-chloro-2-(5-methyl-4-((methylamino)methyl)-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide

Step 1: A 1-dram vial was charged with4-tert-butyl-N-(4-chloro-2-(4-iodo-5-methyl1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide (synthesized accordingto general procedure P, 200 mg, 0.38 mmol), tributyl(vinyl)tin (144 mg,0.45 mmol), bis(triphenylphosphine) palladium (II) dichloride (catalyticquantity), and toluene (1.5 mL). The suspension was heated to 100° C.and stirred 10 hours. The crude reaction was subsequently concentratedin vacuo and purified by column chromatography to afford the desiredvinyl-substituted triazole containing some residual tin by-products.

Step 2: To the above sulfonamide (135 mg, 0.31 mmol) in a 1-dram vialwas added osmium tetroxide (64 mg, 2.5% in tBuOH), pyridine (50 μL, 0.62mmol), and 3 mL of a 3:1 dioxane/water solution. Sodium periodate (268mg, 1.25 mmol) was slowly added to the mixture and the reaction wasstirred at ambient temperature overnight. The following day, the crudereaction was concentrated in vacuo and purified by column chromatographyto produce the desired aldehyde.

Step 3: A 1-dram vial was charged with the above aldehyde (10 mg, 0.023mmol), methylamine (23 μL, 2 M in THF), and methylene chloride (0.3 mL).The solution was stirred 30 minutes at room temperature, followed by theaddition of sodium triacetoxyborohydride (10 mg, 0.046 mmol). Theresultant mixture was stirred for 10 hours, concentrated in vacuo, andpurified by preparative TLC to afford the desired disubstitutedtriazole: MS (ES) M+H expected 448.2, found 448.4.

General Procedure II

Example4-tert-Butyl-N-(4-chloro-2-(5-methyl-4-(thiazol-2-yl)-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide

A 1-dram vial was charged with4-tert-butyl-N-(4-chloro-2-(4-iodo-5-methyl1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide (synthesized accordingto general procedure P, 250 mg, 0.047 mmol), Pd(PPh₃)₄ (11 mg, 0.0099mmol), and 2-thiazolezinc bromide (1 mL, 0.5 M in THF). The solution washeated to 90° C. and stirred for 10 hours. The crude reaction wassubsequently purified by preparative TLC to produce4-tert-butyl-N-(4-chloro-2-(5-methyl-4-(thiazol-2-yl)-1H-1,2,3-triazol-1-yl)phenyl)benzenesulfonamide:MS (ES) M+H expected 488.1, found 488.4.

General Procedure JJ

Example1-[2-(4-tert-Butyl-benzenesulfonylamino)-5-chloro-phenyl]-5-methyl-1H-[1,2,3]triazole-4-carboxylicacid

3 N NaOH (0.1 mL) was added to1-[2-(4-tert-butyl-benzenesulfonylamino)-5-chloro-phenyl]-5-methyl-1H-[1,2,3]triazole-4-carboxylicacid methyl ester (synthesized according to general procedure GG, 22 mg,0.047 mmol) in THF and the resultant reaction mixture stirred at 60° C.overnight. The following day, the reaction mixture was concentrated todryness and purified by preparative TLC to generate the title compound:MS (ES) M+H expected 449.1, found 449.3.

General Procedure KK

Example4-tert-Butyl-N-[4-chloro-2-(5-methyl-4-oxazol-2-yl-[1,2,3]triazol-1-yl)-phenyl]-benzenesulfonamide

To a cooled (−78° C.) solution of n-BuLi (0.5 mL, 2.5 M solution inhexanes) in THF (3 mL) was added oxazole (0.1 mL, 1.5 mmol) via dropwiseaddition and the solution was stirred for 30 minutes. ZnCl₂ solution(3.9 mL, 0.5 M in THF) was then added and the reaction mixture waswarmed to room temperature and stirred an additional 2 hours. Pd(PPh₃)₄(20 mg, 0.015 mmol) and4-tert-butyl-N-[4-chloro-2-(4-iodo-5-methyl-[1,2,3]triazol-1-yl)-phenyl]-benzenesulfonamide(synthesized according to general procedure P, 77 mg, 0.15 mmol) werethen added and the reaction mixture was heated at 80° C. overnight. Thereaction mixture was subsequently diluted with EtOAc (25 mL) and thecombined organics were washed with water (20 mL), dried (Na₂SO₄), andconcentrated in vacuo. The crude product was purified by preparative TLCto afford the title compound: MS (ES) M+H expected 472.1, found 472.0.

General Procedure LL

Example4-tert-Butyl-N-[4-chloro-2-(4-hydroxymethyl-pyrazol-1-yl)-phenyl]-benzenesulfonamide

To an ice cold solution of1-[2-(4-tert-butyl-benzenesulfonylamino)-5-chloro-phenyl]-1H-pyrazole-4-carboxylicacid ethyl ester (synthesized according to general procedure D, 220 mg,0.47 mmol) in THF (5 mL) was added LiAlH₄ (1.0 mL, 2.4 M solution inTHF) dropwise and the resultant reaction mixture was stirred for onehour at room temperature. Saturated Na₂SO₄ solution (3 mL) wassubsequently added slowly at 0° C. and the precipitated solid wasfiltered through celite and washed thoroughly with EtOAc (100 mL). Thefiltrate was dried over Na₂SO₄, concentrated in vacuo, and purified byautomated flash chromatography to afford the title compound: MS (ES) M+Hexpected 420.1, found 420.1.

General Procedure MM

Example4-tert-Butyl-N-[4-chloro-2-(4-methylaminomethyl-pyrazol-1-yl)-phenyl]-benzenesulfonamide

Step 1: To a solution of4-tert-butyl-N-[4-chloro-2-(4-hydroxymethyl-pyrazol-1-yl)-phenyl]-benzenesulfonamide(synthesized according to general procedure LL, 31 mg, 0.074 mmol) inCH₂Cl₂ (3 mL) was added Dess-Martin periodinane (34 mg, 0.33 mmol) andthe reaction was stirred for 3 hours at room temperature. 10% Na₂S₂O₃ (5mL) and saturated aqueous NaHCO₃ (5 mL) were added sequentially and themixture was stirred an additional 30 minutes. The aqueous layer wassubsequently separated and extracted with EtOAc (2×25 mL). The combinedorganic layers were washed with saturated aqueous NaHCO₃ solution (20mL) and brine (20 mL), dried (anhydrous Na₂SO₄), and concentrated invacuo to afford4-tert-butyl-N-[4-chloro-2-(4-formyl-pyrazol-1-yl)-phenyl]-benzenesulfonamidewhich was used for further transformation without purification.

Step 2: The above aldehyde was converted to4-tert-butyl-N-[4-chloro-2-(4-methylaminomethyl-pyrazol-1-yl)-phenyl]-benzenesulfonamideaccording to general procedure HH, step 3: MS (ES) M+H expected 433.1,found 433.4.

General Procedure NN

Example Ethyl1-(2-(4-tert-butylphenylsulfonamido)-5-chlorophenyl)-5-methyl-1H-pyrazole-4-carboxylate

Step 1: A 20 mL vial was charged with 4-chloro-2-fluoro-1-nitrobenzene(176 mg, 1.0 mmol), hydrazine (50 μL, 1.0 mmol) and EtOH (3.0 mL). Thereaction was stirred overnight, during which the product precipitatedfrom solution. The resultant solid was filtered, washed with coldethanol, and dried in vacuo to afford the desired aryl hydrazine as itshydrofluoride salt.

Step 2: To the above hydrazine (736 mg, 3.55 mmol) in a 25 mLround-bottom flask was added ethyl2-((dimethylamino)methylene)-3-oxobutanoate (657 mg, 3.55 mmol) and EtOH(7 mL). The solution was heated to 65° C. and stirred overnight. Thefollowing day, the crude reaction was concentrated in vacuo and purifiedby column chromatography to produce the desired pyrazole.

Step 3: The bicyclic pyrazole (448 mg, 1.45 mmol) was dissolved in AcOH(15 mL) and the solution was heated to 60° C. To the rapidly stirringsolution was added Fe (162 mg, 2.89 mmol) in two portions and thereaction was stirred overnight. The following day, the acetic acid wasremoved in vacuo and the residue was partitioned with methylene chlorideand water, during which significant insoluble material persisted. Theaqueous layer was extracted three times with methylene chloride, thecombined organics dried over sodium sulfate, and concentrated in vacuo.The resultant residue was purified by automated silica gelchromatography to afford the desired aniline.

Step 4: The above aniline (96 mg, 0.34 mmol) was sulfonylated accordingto general procedure G to generate ethyl1-(2-(4-tert-butylphenylsulfonamido)-5-chlorophenyl)-5-methyl-1H-pyrazole-4-carboxylate:MS (ES) M+H expected 476.1, found 476.4.

General Procedure OO

Example 1,1-Dimethyl-3-oxo-1,3-dihydro-isobenzofuran-5-sulfonic acid(4-chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-amide

A 4 mL vial was charged with4-(4-chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenylsulfamoyl)-2-cyano-benzoicacid methyl ester (synthesized according to general procedure G, 23 mg,0.05 mmol) and 1.5 mL THF. The slurry was cooled to −40° C. in a dryice-acetonitrile bath and 3.0 M methylmagnesium chloride in Et₂O (83 μL,0.25 mmol) was added dropwise. The resultant mixture was stirred fivehours, during which it was warmed to 0° C. 2 N HCl (1.5 mL) wassubsequently added to reaction mixture and it was stirred at roomtemperature overnight. The reaction mixture was then purified byreversed phase HPLC to afford1,1-dimethyl-3-oxo-1,3-dihydro-isobenzofuran-5-sulfonic acid(4-chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-amide: MS (ES)M+H expected 470.0, found 470.0.

General Procedure PP

ExampleN-(4-Chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-3-fluoro-4-(1-hydroxy-1-methyl-ethyl)-benzenesulfonamidesodium salt

Step 1: To 4-chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenylamine(153.5 mg, 0.626 mmol) in pyridine (2 mL) was added4-chlorosulfonyl-2-fluoro-benzoic acid ethyl ester (200 mg, 0.752 mmol)followed by methanesulfonyl chloride (32 μL, 0.47 mmol) at 0° C. under anitrogen atmosphere. The resultant reaction mixture was allowed to warmto room temperature and stirred for overnight. The following day,reaction mixture was diluted with EtOAc (25 mL), washed with 2N HCl(2×15 mL), dried (Na₂SO₄) and evaporated. The resulting bis-sulfonamidescrude mixture was treated with 1 N TBAF (in THF, 2 mL) at roomtemperature for 1 hour. The reaction mixture was then diluted with EtOAc(25 mL), washed with 2 N HCl (2×15 mL), water (10 mL), brine (10 mL),dried (Na₂SO₄) and evaporated. The resulting crude product was purifiedby SiO₂ chromatography using 50→100% EtOAc in hexanes solvent system toobtain4-(4-chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenylsulfamoyl)-2-fluoro-benzoicacid ethyl ester.Step 2: The title compound was prepared via conversion from its ethylester according to general procedure Y: MS (ES) M+Na expected 484.0,found 484.0.

Measuring Efficacy of Chemokine Modulators

In Vitro Assays

A variety of assays can be used to evaluate the compounds providedherein, including signaling assays, chemotaxis (migration assays),ligand binding assays, and other assays of cellular response. Chemokinereceptor signaling assays can be used to measure the ability of acompound, such as a potential CCR9 antagonist, to block CCR9 ligand-(e.g. TECK)-induced signaling. A migration assay can be used to measurethe ability of a compound of interest, such as a possible chemokineantagonist, to block chemokine-mediated cell migration in vitro. Thelatter is believed to resemble chemokine-induced cell migration in vivo.A ligand binding assay can be used to measure the ability of a compound,such as a potential CCR9 antagonist, to block the interaction of TECKwith its receptor.

In a suitable assay, a chemokine protein (whether isolated orrecombinant) is used which has at least one property, activity, orfunctional characteristic of a mammalian chemokine protein. The propertycan be a binding property (to, for example, a ligand or inhibitor), asignaling activity (e.g., activation of a mammalian G protein, inductionof rapid and transient increase in the concentration of cytosolic freecalcium ion), cellular response function (e.g., stimulation ofchemotaxis or inflammatory mediator release by leukocytes), and thelike.

The assay can be a cell-based assay that utilizes cells stably ortransiently transfected with a vector or expression cassette having anucleic acid sequence that encodes the chemokine receptor. Cell linesnaturally expressing the chemokine can also be used. The cells aremaintained under conditions appropriate for expression of the receptorand are contacted with a putative agent under conditions appropriate forbinding to occur. Binding can be detected using standard techniques. Forexample, the extent of binding can be determined relative to a suitablecontrol (for example, relative to background in the absence of aputative agent, or relative to a known ligand). Optionally, a cellularfraction, such as a membrane fraction, containing the receptor can beused in lieu of whole cells.

Detection of binding or complex formation can be detected directly orindirectly. For example, the putative agent can be labeled with asuitable label (e.g., fluorescent label, chemiluminescent label, isotopelabel, enzyme label, and the like) and binding can be determined bydetection of the label. Specific and/or competitive binding can beassessed by competition or displacement studies, using unlabeled agentor a ligand (e.g., TECK) as a competitor.

Binding inhibition assays can be used to evaluate the present compounds.In these assays, the compounds are evaluated as inhibitors of ligandbinding using, for example, TECK. In another embodiment, the CCR9receptor is contacted with a ligand such as TECK and a measure of ligandbinding is made. The receptor is then contacted with a test agent in thepresence of a ligand (e.g., TECK) and a second measurement of binding ismade. A reduction in the extent of ligand binding is indicative ofinhibition of binding by the test agent. The binding inhibition assayscan be carried out using whole cells which express the chemokine, or amembrane fraction from cells which express the chemokine.

The binding of a G protein coupled receptor by, for example, an agonist,can result in a signaling event by the receptor. Accordingly, signalingassays can also be used to evaluate the compounds of the presentinvention and induction of signaling function by an agent can bemonitored using any suitable method. For example, G protein activity,such as hydrolysis of GTP to GDP, or later signaling events triggered byreceptor binding can be assayed by known methods (see, for example,PCT/US97/15915; Neote et al., Cell, 72:415-425 (1993); Van Riper et al.,J. Exp. Med., 177:851-856 (1993) and Dahinden et al., J. Exp. Med.,179:751-756 (1994)).

Chemotaxis assays can also be used to assess receptor function andevaluate the compounds provided herein. These assays are based on thefunctional migration of cells in vitro or in vivo induced by an agent,and can be used to assess the binding and/or effect on chemotaxis ofligands, inhibitors, or agonists. A variety of chemotaxis assays areknown in the art, and any suitable assay can be used to evaluate thecompounds of the present invention. Examples of suitable assays includethose described in PCT/US97/15915; Springer et al., WO 94/20142; Bermanet al., Immunol. Invest., 17:625-677 (1988); and Kavanaugh et al., J.Immunol., 146:4149-4156 (1991)).

Calcium signaling assays measure calcium concentration over time,preferably before and after receptor binding. These assays can be usedto quantify the generation of a receptor-signaling mediator, Ca⁺⁺,following receptor binding (or absence thereof). These assays are usefulin determining the ability of a compound, such as those of the presentinvention, to generate the receptor signaling mediator by binding to areceptor of interest. Also, these assays are useful in determining theability of a compound, such as those of the present invention, toinhibit generation of the receptor signaling mediator by interferingwith binding between a receptor of interest and a ligand.

In calcium signaling assays used to determine the ability of a compoundto interfere with binding between a chemokine receptor and a knownchemokine ligand, chemokine receptor-expressing cells (CCR9-expressingcells such as T cell line MOLT-4 cells) are first incubated with acompound of interest, such as a potential chemokine antagonist, atincreasing concentrations. The cell number can be from 10⁵ to 5×10⁵cells per well in a 96-well microtiter plate. The concentration of thecompound being tested may range from 0 to 100 μM. After a period ofincubation (which can range from 5 to 60 minutes), the treated cells areplaced in a Fluorometric Imaging Plate Reader (FLIPR®) (available fromMolecular Devices Corp., Sunnyvale, Calif.) according to themanufacturer's instruction. The FLIPR® system is well known to thoseskilled in the art as a standard method of performing assays. The cellsare then stimulated with an appropriate amount of the chemokine ligand(TECK for CCR9) at 5-100 nM final concentration, and the signal ofintracellular calcium increase (also called calcium flux) is recorded.The efficacy of a compound as an inhibitor of binding between thechemokine and the ligand can be calculated as an IC₅₀ (the concentrationneeded to cause 50% inhibition in signaling) or IC₉₀ (at 90%inhibition).

In vitro cell migration assays can be performed (but are not limited tothis format) using the 96-well microchamber (called ChemoTX™). TheChemoTX™ system is well known to those skilled in the art as a type ofchemotactic/cell migration instrument. In this assay, CCR9-expressingcells (such as MOLT-4) are first incubated with a compound of interest,such as a possible CCR9 antagonist at increasing concentrations.Typically, fifty thousand cells per well are used, but the amount canrange from 10³-10⁶ cells per well. The chemokine ligand (for example,CCR9 ligand TECK, typically at 50 nM (but can range from 5-100 nM)), isplaced at the lower chamber and the migration apparatus is assembled.Twenty microliters of test compound-treated cells are then placed ontothe membrane. Migration is allowed to take place at 37° C. for a periodof time, typically 2.5 hours for CCR9. At the end of the incubation, thenumber of cells that migrated across the membrane into the lower chamberis then quantified. The efficacy of a compound as an inhibitor ofchemokine-mediated cell migration is calculated as an IC₅₀ (theconcentration needed to reduce cell migration by 50%) or IC₉₀ (for 90%inhibition).

In Vivo Efficacy Models for Human IBD

T cell infiltration into the small intestine and colon have been linkedto the pathogenesis of human inflammatory bowel diseases which includeCoeliac disease, Crohn's disease and ulcerative colitis. Blockingtrafficking of relevant T cell populations to the intestine is believedto be an effective approach to treat human IBD. CCR9 is expressed ongut-homing T cells in peripheral blood, elevated in patients with smallbowel inflammation such as Crohn's disease and Coeliac disease. CCR9ligand TECK is expressed in the small intestine. It is thus believedthat this ligand-receptor pair plays a role in IBD development bymediating migration of T cells to the intestine. Several animal modelsexist and can be used for evaluating compounds of interest, such aspotential CCR9 antagonists, for an ability to affect such T cellmigration and/or condition or disease, which might allow efficacypredictions of antagonists in humans.

Animal Models with Pathology Similar to Human Ulcerative Colitis

A murine model described by Panwala and coworkers (Panwala et al., J.Immunol., 161(10):5733-44 (1998)) involves genetic deletion of themurine multi-drug resistant gene (MDR). MDR knockout mice (MDR−/−) aresusceptible to developing a severe, spontaneous intestinal inflammationwhen maintained under specific pathogen-free facility conditions. Theintestinal inflammation seen in MDR−/− mice has a pathology similar tothat of human inflammatory bowel disease (IBD) and is defined by Th1type T cells infiltration into the lamina propria of the largeintestine.

Another murine model was described by Davidson et al., J Exp Med.,184(1):241-51 (1986). In this model, the murine IL-10 gene was deletedand mice rendered deficient in the production of interleukin 10(IL-10−/−). These mice develop a chronic inflammatory bowel disease(IBD) that predominates in the colon and shares histopathologicalfeatures with human IBD.

Another murine model for IBD has been described by Powrie et al., Int.Immunol., 5(11):1461-71 (1993), in which a subset of CD4+ T cells(called CD45RB (high)) from immunocompetent mice are purified andadoptively transferred into immunodeficient mice (such as C.B-17 scidmice). The animal restored with the CD45RBhighCD4+ T cell populationdeveloped a lethal wasting disease with severe mononuclear cellinfiltrates in the colon, pathologically similar with human IBD.

Murine Models with Pathology Similar to Human Crohn's Disease

The TNF ARE(−/−) model. The role of TNF in Crohn's disease in human hasbeen demonstrated more recently by success of treatment using anti-TNFalpha antibody by Targan et al., N. Engl. J Med., 337(15):1029-35(1997). Mice with aberrant production of TNF-alpha due to geneticalteration in the TNF gene (ARE−/−) develop Crohn's-like inflammatorybowel diseases (see Kontoyiannis et al., Immunity, 10(3):387-98 (1999)).

The SAMP/yit model. This model is described by Kosiewicz et al., J Clin.Invest., 107(6):695-702 (2001). The mouse strain, SAMP/Yit,spontaneously develops a chronic inflammation localized to the terminalileum. The resulting ileitis is characterized by massive infiltration ofactivated T lymphocytes into the lamina propria, and bears a remarkableresemblance to human Crohn's disease.

Examples of In Vitro Assay

Reagents

MOLT-4 cells were obtained from the American Type Culture Collection(Manassas, Va.) and cultured in RPMI tissue culture medium supplementedwith 10% fetal calf serum (FCS) in a humidified 5% CO₂ incubator at 37°C. Recombinant human chemokine proteins TECK was obtained from R&DSystems (Minneapolis, Minn.). ChemoTX® chemotaxis microchambers werepurchased from Neuro Probe (Gaithersburg, Md.). CyQUANT® cellproliferation kits were purchased from Molecular Probes (Eugene, Oreg.).Calcium indicator dye Fluo-4 AM was purchased from Molecular Devices(Mountain View, Calif.).

Chemotaxis Assay

Chemotaxis assay was used to determine the efficacy of potentialreceptor antagonists in blocking migration mediated through chemokines(such as CCR9). This assay was routinely performed using the ChemoTX®microchamber system with a 5-μm pore-sized polycarbonate membrane. Tobegin such an assay, chemokine expressing cells (such as MOLT-4 cellsfor CCR9 assay) were harvested by centrifugation of cell suspension at1000 RPM on a GS-6R Beckman centrifuge. The cell pellet was resuspendedin chemotaxis buffer (HBSS with 0.1% BSA) at 5×10⁶ cells/mL for CCR9assay. Test compounds at desired concentrations were prepared from 10 mMstock solutions by serial dilutions in chemotaxis buffer. An equalvolume of cells and compounds were mixed and incubated at roomtemperature for 15 minutes. Afterwards, 20 μL of the mixture wastransferred onto the porous membrane of a migration microchamber, with29 μL of chemokine ligand (50 nm chemokine TECK protein for CCR9 assay)placed at the lower chamber. Following an incubation at 37° C.(150-minute for CCR9), during which cells migrated against the chemokinegradient, the assay was terminated by removing the cell drops from atopthe filter. To quantify cells migrated across the membrane, 5 μL of 7×CYQUANT® solution was added to each well in the lower chamber, and thefluorescence signal measured on a Spectrafluor Plus fluorescence platereader (TECAN, Durham, N.C.). The degree of inhibition was determined bycomparing migration signals between compound-treated and untreatedcells. IC₅₀ calculation was further performed by non-linear squaresregression analysis using Graphpad Prism (Graphpad Software, San Diego,Calif.).

In Vivo Efficacy

A 17-day study of type II collagen-induced arthritis is conducted toevaluate the effects of a modulator on arthritis-induced clinical ankleswelling. Rat collagen-induced arthritis is an experimental model ofpolyarthritis that has been widely used for preclinical testing ofnumerous anti-arthritic agents (see Trentham et al., J. Exp. Med.146(3):857-868 (1977), Bendele et al., Toxicologic Pathol. 27:134-142(1999), Bendele et al., Arthritis. Rheum. 42:498-506 (1999)). Thehallmarks of this model are reliable onset and progression of robust,easily measurable polyarticular inflammation, marked cartilagedestruction in association with pannus formation and mild to moderatebone resorption and periosteal bone proliferation.

Female Lewis rats (approximately 0.2 kilograms) are anesthetized withisoflurane and injected with Freund's Incomplete Adjuvant containing 2mg/mL bovine type II collagen at the base of the tail and two sites onthe back on days 0 and 6 of this 17-day study. The test modulator isdosed daily by sub-cutaneous injection from day 9 to day 17 at a dose of100 mg/kg and a volume of 1 mL/kg in the following vehicle (24.5%Cremaphore EL, 24.5% common oil, 1% Benzylalcohol and 50% Distilledwater). Caliper measurements of the ankle joint diameter are takendaily, and reducing joint swelling is taken as a measure of efficacy.

The MDR1a-knockout mice, which lack the P-glycoprotein gene,spontaneously develop colitis under specific pathogen-free condition.The pathology in these animals has been characterized as Th1-type Tcell-mediated inflammation similar to ulcerative colitis in humans.Disease normally begins to develop at around 8-10 weeks after birth.However the ages at which disease emerges and the ultimate penetrancelevel often vary considerably among different animal facilities.

In a study using the MDR1a-knockout mice, a CCR9 antagonist is evaluatedby prophylactic administration for its ability to delay disease onset.Female mice (n=34) are dosed with 50 mg/kg twice a day by subcutaneousinjections for 14 consecutive weeks starting at age 10 weeks. The studyis evaluated for IBD-associated growth retardation.

Evaluation of a Test Modulator in a Rat Model of Thioglycollate-inducedPeritoneal Inflammation

A 2-day study of thioglycollate-induced inflammation is conducted toevaluate the effects of the test modulator. The hallmarks of this modelare reliable onset and progression of robust, easily measurableinflammatory cellular infiltrate. For the induction of inflammatoryperitonitis in Lewis rats, Brewer-Thioglycollate (1.0 mL, 4% solution indistilled water) is injected intra peritoneal (i.p.). Before thisinjection, the treatment group received test modulator or vehicle andthe control group received the same volume of PBS as i.p. injection.After 2 days, a peritoneal lavage is performed with ice-cold PBS(phosphate-buffered saline) containing 1 mM EDTA. The recovered cellsare counted with a cell counter (Coulter Counter; CoulterPharmaceutical, Palo Alto, Calif.) and monocytes/macrophages wereidentified by flow cytometry using light-scatter properties.

Evaluation of a Test Modulator in a Mouse Model of Bacterial Infection

A 1-day study of streptococcus pneumoniae infection is conducted toevaluate the effects of the test modulator. The model measures bacterialinfection and spread in an animal following pulmonary infection withlive bacterial cultures, measured by inflammatory cellular infiltrate,and assessment of bacterial burden. C57/B6 mice are inoculated intranasally with LD50 400 CFU at day 0. Groups are either test modulator orvehicle control treated 1 day prior to bacterial inoculation and twicedaily throughout the study. Bacterial burden is measured at 24 hours byplating serial dilutions of homogenized lung tissue on agar plates andcounting colonies.

It is therefore intended that the foregoing detailed description beregarded as illustrative rather than limiting, and that it be understoodthat it is the following claims, including all equivalents, that areintended to define the spirit and scope of this invention.

1. A compound that isN-(4-Chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-4-(1-hydroxy-1-methyl-ethyl)-benzene-sulfonamide,or a salt thereof.
 2. A compound that isN-(4-Chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-4-(1-hydroxy-1-methyl-ethyl)-benzene-sulfonamide.3. A compound that isN-(4-Chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-4-(1-hydroxy-1-methyl-ethyl)-benzene-sulfonamidesodium salt.
 4. A composition comprising a pharmaceutically acceptablecarrier and a compound of claim
 1. 5. A composition comprising apharmaceutically acceptable carrier and a compound of claim
 2. 6. Acomposition comprising a pharmaceutically acceptable carrier and acompound of claim 3.